Comprehensive Physiology Wiley Online Library

Uterine Vascular Control Preconception and During Pregnancy

Full Article on Wiley Online Library



Abstract

Successful pregnancy and reproduction are dependent on adequate uterine blood flow, placental perfusion, and vascular responsivity to fetal demands. The ability to support pregnancy centers on systemic adaptation and endometrial preparation through decidualization, embryonic implantation, trophoblast invasion, arterial/arteriolar reactivity, and vascular remodeling. These adaptations occur through responsiveness to endocrine signaling and local uteroplacental mediators. The purpose of this article is to highlight the current knowledge associated with vascular remodeling and responsivity during uterine preparation for and during pregnancy. We focus on maternal cardiovascular systemic and uterine modifications, endometrial decidualization, implantation and invasion, uterine and spiral artery remodeling, local uterine regulatory mechanisms, placentation, and pathological consequences of vascular dysfunction during pregnancy. © 2021 American Physiological Society. Compr Physiol 11:1871‐1893, 2021.

Figure 1. Figure 1. Uterine gross anatomy and blood supply. (A) Human uterus. View of the human female reproductive tract. Human uterine blood flow is derived from the ovarian and uterine arteries. These arteries branch to form the arcuate artery, allowing for greater tissue perfusion. The arcuate arteries subsequently branch to the radial artery, straight/basal arterioles, and spiral/preplacental arterioles. (B) Rodent uterus. The rodent uterus is a dual‐horn, bilateral organ allowing for multiple pup litters. The vascular architecture between the human and rodent uteri is very similar, making the rodent an ideal model to assess reproductive physiology. (C) Rabbit uterus. The rabbit also has a duplex uterus, with two independent uterine horns combining at the cervix to allow for multiple fetus litters. The vasculature is very similar to that of the rodent, with their main artery supply via the ovarian artery, with bifurcates to the ovarian and uterine branches, the uterine artery supplying the distal uterine horn, and the vaginal artery. Secondary arteries may form analogous to human arcuate arteries; arcuate and radial arteries provide blood supply to the myometrium and preplacental arterioles. (D) Sheep uterus. The sheep uterus consists of two conjoined cavities with a short uterine body. The vasculature is similar to that of humans with the main source of blood flow supplied by the uterine artery. The ovary is supplied by the ovarian artery. The uterine artery branches, giving rise to anastomose, which acts in a similar fashion to human arcuate arteries. These branches give rise to coiled secondary radial arteries that supply the myometrium and preplacental vessels.
Figure 2. Figure 2. Vasodilation during the estrous cycle and pregnancy. Vascular reactivity to endothelium‐dependent (A) or ‐independent (B) modulators of vascular smooth muscle relaxation varies during the phases of the rodent estrous cycle (black lines). Perturbations to maternal homeostasis through natural (e.g., circadian rhythm disturbances or noise pollution) or chemical (e.g., air or water pollution) exposures may make these variations more pronounced (red lines). Reprinted, with permission, from Stapleton PA, et al., 2018 207.
Figure 3. Figure 3. Decidualization. Representation of decidualization of the human endometrium. Morphological and functional differentiation of endometrial stromal cells (ESCs), especially during the implantation window, is required for successful pregnancy outcome. Reprinted, with permission, from Murakami K, et al., 2018 150.
Figure 4. Figure 4. Trophoblastic invasion. Trophoblast invasion and spiral artery remodeling in healthy pregnancy. Reprinted, with permission, from Soares MJ, et al., 2014 202.
Figure 5. Figure 5. Spiral artery remodeling. Spiral artery remodeling continues throughout pregnancy into the second and third trimesters to provide increased blood flow to the growing fetus. Pregnancies that suffer from ischemic placental disease may demonstrate shallow trophoblast invasion and defective vascular remodeling, thus leading to reduced maternal blood flow and compromised fetal growth. Reprinted, with permission, from Roberts JM, 2014 177.
Figure 6. Figure 6. Circulation of the intervillous space. Maternal blood enters the intervillous space from uterine spiral arteries and flows around terminal villi. After the exchange of oxygen and nutrients, the umbilical vein carries oxygenated and nutrient‐rich fetal blood to the fetal circulation. Reprinted, with permission, from Red‐Horse K, et al., 2005 172.
Figure 7. Figure 7. Uteroplacental blood flow. Schematic depicting the increase in uterine blood flow through gestation in response to fetal growth. Reprinted, with permission, from Greiss FC, et al., 1972 80.
Figure 8. Figure 8. Uteroplacental and fetoplacental circulation. The uterine, radial, and spiral arteries/arterioles perfuse the placenta with nutrient‐rich blood. The fetoplacental circulation includes the umbilical cord and the blood vessels within the placenta that carry fetal blood. Umbilical arteries carry deoxygenated and nutrient‐depleted fetal blood from the fetus to the villous core fetal vessels where the exchange of oxygen and nutrients takes place. The umbilical cord returns oxygenated and nutrient‐rich fetal blood to the fetal circulation. Adapted, with permission, from D'Errico JN, et al., 2019 47,48.
Figure 9. Figure 9. Uteroplacental growth. The uterine vasculature and muscle remodel significantly to sustain a successful pregnancy. This photograph shows the age‐matched uterine horn from pregnant (A) and nonpregnant (B) rats to depict vascular growth during pregnancy. Reprinted, with permission, from Mandala M and Osol G, 2012 129.
Figure 10. Figure 10. Uterine vascular hypertrophic remodeling. Vascular remodeling may be normal or pathologic. Hypertrophic vascular remodeling describes an increase in luminal wall thickness. This remodeling may be inward (i.e., narrowing the vascular lumen), eutrophic (i.e., maintaining luminal circumference), or outward (i.e., expanding the vascular lumen). The remodeling in the uterine circulation during gestation may be described as outward hypertrophic, thereby increasing both the wall area and the luminal cross section.
Figure 11. Figure 11. Uterine vascular reactivity. Local vascular responses are altered during pregnancy, shifting toward vascular smooth muscle (VSM) relaxation and subsequent vasodilation. This shift is depicted by (A) reduced responsiveness to phenylephrine, a vasoconstrictor, (B) heightened response to sodium nitroprusside, an endothelium‐independent vasodilator in arcuate arteries from pregnant rats compared to nonpregnant, and (C) no change in responsivity to acetylcholine, an endothelium‐dependent vasodilator between the arteries excised from pregnant and nonpregnant rats. Reprinted, with permission, from Fuller R, et al., 2011 62.


Figure 1. Uterine gross anatomy and blood supply. (A) Human uterus. View of the human female reproductive tract. Human uterine blood flow is derived from the ovarian and uterine arteries. These arteries branch to form the arcuate artery, allowing for greater tissue perfusion. The arcuate arteries subsequently branch to the radial artery, straight/basal arterioles, and spiral/preplacental arterioles. (B) Rodent uterus. The rodent uterus is a dual‐horn, bilateral organ allowing for multiple pup litters. The vascular architecture between the human and rodent uteri is very similar, making the rodent an ideal model to assess reproductive physiology. (C) Rabbit uterus. The rabbit also has a duplex uterus, with two independent uterine horns combining at the cervix to allow for multiple fetus litters. The vasculature is very similar to that of the rodent, with their main artery supply via the ovarian artery, with bifurcates to the ovarian and uterine branches, the uterine artery supplying the distal uterine horn, and the vaginal artery. Secondary arteries may form analogous to human arcuate arteries; arcuate and radial arteries provide blood supply to the myometrium and preplacental arterioles. (D) Sheep uterus. The sheep uterus consists of two conjoined cavities with a short uterine body. The vasculature is similar to that of humans with the main source of blood flow supplied by the uterine artery. The ovary is supplied by the ovarian artery. The uterine artery branches, giving rise to anastomose, which acts in a similar fashion to human arcuate arteries. These branches give rise to coiled secondary radial arteries that supply the myometrium and preplacental vessels.


Figure 2. Vasodilation during the estrous cycle and pregnancy. Vascular reactivity to endothelium‐dependent (A) or ‐independent (B) modulators of vascular smooth muscle relaxation varies during the phases of the rodent estrous cycle (black lines). Perturbations to maternal homeostasis through natural (e.g., circadian rhythm disturbances or noise pollution) or chemical (e.g., air or water pollution) exposures may make these variations more pronounced (red lines). Reprinted, with permission, from Stapleton PA, et al., 2018 207.


Figure 3. Decidualization. Representation of decidualization of the human endometrium. Morphological and functional differentiation of endometrial stromal cells (ESCs), especially during the implantation window, is required for successful pregnancy outcome. Reprinted, with permission, from Murakami K, et al., 2018 150.


Figure 4. Trophoblastic invasion. Trophoblast invasion and spiral artery remodeling in healthy pregnancy. Reprinted, with permission, from Soares MJ, et al., 2014 202.


Figure 5. Spiral artery remodeling. Spiral artery remodeling continues throughout pregnancy into the second and third trimesters to provide increased blood flow to the growing fetus. Pregnancies that suffer from ischemic placental disease may demonstrate shallow trophoblast invasion and defective vascular remodeling, thus leading to reduced maternal blood flow and compromised fetal growth. Reprinted, with permission, from Roberts JM, 2014 177.


Figure 6. Circulation of the intervillous space. Maternal blood enters the intervillous space from uterine spiral arteries and flows around terminal villi. After the exchange of oxygen and nutrients, the umbilical vein carries oxygenated and nutrient‐rich fetal blood to the fetal circulation. Reprinted, with permission, from Red‐Horse K, et al., 2005 172.


Figure 7. Uteroplacental blood flow. Schematic depicting the increase in uterine blood flow through gestation in response to fetal growth. Reprinted, with permission, from Greiss FC, et al., 1972 80.


Figure 8. Uteroplacental and fetoplacental circulation. The uterine, radial, and spiral arteries/arterioles perfuse the placenta with nutrient‐rich blood. The fetoplacental circulation includes the umbilical cord and the blood vessels within the placenta that carry fetal blood. Umbilical arteries carry deoxygenated and nutrient‐depleted fetal blood from the fetus to the villous core fetal vessels where the exchange of oxygen and nutrients takes place. The umbilical cord returns oxygenated and nutrient‐rich fetal blood to the fetal circulation. Adapted, with permission, from D'Errico JN, et al., 2019 47,48.


Figure 9. Uteroplacental growth. The uterine vasculature and muscle remodel significantly to sustain a successful pregnancy. This photograph shows the age‐matched uterine horn from pregnant (A) and nonpregnant (B) rats to depict vascular growth during pregnancy. Reprinted, with permission, from Mandala M and Osol G, 2012 129.


Figure 10. Uterine vascular hypertrophic remodeling. Vascular remodeling may be normal or pathologic. Hypertrophic vascular remodeling describes an increase in luminal wall thickness. This remodeling may be inward (i.e., narrowing the vascular lumen), eutrophic (i.e., maintaining luminal circumference), or outward (i.e., expanding the vascular lumen). The remodeling in the uterine circulation during gestation may be described as outward hypertrophic, thereby increasing both the wall area and the luminal cross section.


Figure 11. Uterine vascular reactivity. Local vascular responses are altered during pregnancy, shifting toward vascular smooth muscle (VSM) relaxation and subsequent vasodilation. This shift is depicted by (A) reduced responsiveness to phenylephrine, a vasoconstrictor, (B) heightened response to sodium nitroprusside, an endothelium‐independent vasodilator in arcuate arteries from pregnant rats compared to nonpregnant, and (C) no change in responsivity to acetylcholine, an endothelium‐dependent vasodilator between the arteries excised from pregnant and nonpregnant rats. Reprinted, with permission, from Fuller R, et al., 2011 62.
References
 1.Abdo I, George RB, Farrag M, Cerny V, Lehmann C. Microcirculation in pregnancy. Physiol Res 63: 395‐408, 2014.
 2.Acharya G, Sonesson SE, Flo K, Rasanen J, Odibo A. Hemodynamic aspects of normal human feto‐placental (umbilical) circulation. Acta Obstet Gynecol Scand 95: 672‐682, 2016.
 3.Alsip NL, Hornung JW, Henzel MK, Asher EF. Pregnancy‐induced alterations of uterine arteriolar reactivity in the rat: Observations with a new in vivo microcirculatory preparation. Am J Obstet Gynecol 183: 621‐626, 2000.
 4.Anderson SG, Hackshaw BT, Still JG, Greiss FC Jr. Uterine blood flow and its distribution after chronic estrogen and progesterone administration. Am J Obstet Gynecol 127: 138‐142, 1977.
 5.Anderson SG, Still JG, Greiss FC Jr. Differential reactivity of the gravid uterine vasculatures: Effects of norepinephrine. Am J Obstet Gynecol 129: 293‐298, 1977.
 6.Annibale DJ, Rosenfeld CR, Stull JT, Kamm KE. Protein content and myosin light chain phosphorylation in uterine arteries during pregnancy. Am J Phys 259: C484‐C489, 1990.
 7.Apps R, Gardner L, Sharkey AM, Holmes N, Moffett A. A homodimeric complex of HLA‐G on normal trophoblast cells modulates antigen‐presenting cells via LILRB1. Eur J Immunol 37: 1924‐1937, 2007.
 8.Arora S, Veves A, Caballaro AE, Smakowski P, LoGerfo FW. Estrogen improves endothelial function. J Vasc Surg 27: 1141‐1147, 1998.
 9.Assali NS, Nuwayhid B, Brinkman CR 3rd, Tabsh K, Erkkola R, Ushioda E. Autonomic control of the pelvic circulation: In vivo and in vitro studies in pregnant and nonpregnant sheep. Am J Obstet Gynecol 141: 873‐884, 1981.
 10.Atkinson AL, Santolaya‐Forgas J, Blitzer DN, Santolaya JL, Matta P, Canterino J, Oyelese Y. Risk factors for perinatal mortality in patients admitted to the hospital with the diagnosis of placental abruption. J Matern‐Fetal Neonatal Med 28: 594‐597, 2015.
 11.Baergen R. Postpartum Hemorrhage, Subinvolution of the Placental Site, and Placenta Accreta. New York City: Springer US, 2005, p. 190‐207.
 12.Baird DT, Cameron ST, Critchley HO, Drudy TA, Howe A, Jones RL, Lea RG, Kelly RW. Prostaglandins and menstruation. Eur J Obstet Gynecol Reprod Biol 70: 15‐17, 1996.
 13.Banerjee P, Ghosh S, Dutta M, Subramani E, Khalpada J, Roychoudhury S, Chakravarty B, Chaudhury K. Identification of key contributory factors responsible for vascular dysfunction in idiopathic recurrent spontaneous miscarriage. PLoS One 8: e80940, 2013.
 14.Barbagallo M, Dominguez LJ, Licata G, Shan J, Bing L, Karpinski E, Pang PK, Resnick LM. Vascular effects of progesterone: Role of cellular calcium regulation. Hypertension 37: 142‐147, 2001.
 15.Barnea ER. Insight into early pregnancy events: The emerging role of the embryo. Am J Reprod Immunol 51: 319‐322, 2004.
 16.Bartels HC, Postle JD, Downey P, Brennan DJ. Placenta accreta spectrum: A review of pathology, molecular biology, and biomarkers. Dis Markers 2018: 1507674‐1507674, 2018.
 17.Benjamin N, Rymer J, Todd SD, Thom M, Ritter JM. Sensitivity to angiotensin II of forearm resistance vessels in pregnancy. Br J Clin Pharmacol 32: 523‐525, 1991.
 18.Blois SM, Klapp BF, Barrientos G. Decidualization and angiogenesis in early pregnancy: Unravelling the functions of DC and NK cells. J Reprod Immunol 88 (2): 86‐92, 2011.
 19.Boeldt DS, Bird IM. Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia. J Endocrinol 232: R27‐R44, 2017.
 20.Boujedaini N, Liu J, Thuillez C, Cazin L, Mensah‐Nyagan AG. In vivo regulation of vasomotricity by nitric oxide and prostanoids during gestation. Eur J Pharmacol 427: 143‐149, 2001.
 21.Brennan LJ, Morton JS, Davidge ST. Vascular dysfunction in preeclampsia. Microcirculation 21: 4‐14, 2014.
 22.Bulletti C, Jasonni VM, Lubicz S, Flamigni C, Gurpide E. Extracorporeal perfusion of the human uterus. Am J Obstet Gynecol 154: 683‐688, 1986.
 23.Bulmer JN, Innes BA, Levey J, Robson SC, Lash GE. The role of vascular smooth muscle cell apoptosis and migration during uterine spiral artery remodeling in normal human pregnancy. FASEB J 26: 2975‐2985, 2012.
 24.Burton GJ, Charnock‐Jones DS, Jauniaux E. Regulation of vascular growth and function in the human placenta. Reproduction 138: 895‐902, 2009.
 25.Burton GJ, Woods AW, Jauniaux E, Kingdom JC. Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy. Placenta 30: 473‐482, 2009.
 26.Byers MJ, Zangl A, Phernetton TM, Lopez G, Chen DB, Magness RR. Endothelial vasodilator production by ovine uterine and systemic arteries: Ovarian steroid and pregnancy control of ERalpha and ERbeta levels. J Physiol 565: 85‐99, 2005.
 27.Carson DD, Bagchi I, Dey SK, Enders AC, Fazleabas AT, Lessey BA, Yoshinaga K. Embryo implantation. Dev Biol 223: 217‐237, 2000.
 28.Caton D, Abrams RM, Clapp JF, Barron DH. The effect of exogenous progesterone on the rate of blood flow of the uterus of ovariectomized sheep. Q J Exp Physiol Cogn Med Sci 59: 225‐231, 1974.
 29.Chambliss KL, Shaul PW. Estrogen modulation of endothelial nitric oxide synthase. Endocr Rev 23: 665‐686, 2002.
 30.Chang K, Lubo Z. Review article: Steroid hormones and uterine vascular adaptation to pregnancy. Reprod Sci (Thousand Oaks, Calif) 15: 336‐348, 2008.
 31.Chen J, Khalil RA. Matrix metalloproteinases in normal pregnancy and preeclampsia. Prog Mol Biol Transl Sci 148: 87‐165, 2017.
 32.Chennazhi KP, Nayak NR. Regulation of angiogenesis in the primate endometrium: Vascular endothelial growth factor. Semin Reprod Med 27: 80‐89, 2009.
 33.Cicinelli E, Einer‐Jensen N, Galantino P, Alfonso R, Nicoletti R. The vascular cast of the human uterus: From anatomy to physiology. Ann N Y Acad Sci 1034: 19‐26, 2004.
 34.Cipolla M, Osol G. Hypertrophic and hyperplastic effects of pregnancy on the rat uterine arterial wall. Am J Obstet Gynecol 171: 805‐811, 1994.
 35.Cipolla MJ, Binder ND, Osol G. Myoendometrial versus placental uterine arteries: Structural, mechanical, and functional differences in late‐pregnant rabbits. Am J Obstet Gynecol 177: 215‐221, 1997.
 36.Conrad KP. Unveiling the vasodilatory actions and mechanisms of relaxin. Hypertension 56: 2‐9, 2010.
 37.Cooke CL, Davidge ST. Pregnancy‐induced alterations of vascular function in mouse mesenteric and uterine arteries. Biol Reprod 68: 1072‐1077, 2003.
 38.Cross JC, Werb Z, Fisher SJ. Implantation and the placenta: Key pieces of the development puzzle. Science 266: 1508‐1518, 1994.
 39.Cunha GR, Robboy SJ, Kurita T, Isaacson D, Shen J, Cao M, Baskin LS. Development of the human female reproductive tract. Differentiation 103: 46‐65, 2018.
 40.Dafopoulos K, Mademtzis I, Vanakara P, Kallitsaris A, Stamatiou G, Kotsovassilis C, Messinis IE. Evidence that termination of the estradiol‐induced luteinizing hormone surge in women is regulated by ovarian factors. J Clin Endocrinol Metab 91: 641‐645, 2006.
 41.Dalle Lucca JJ, Adeagbo AS, Alsip NL. Oestrous cycle and pregnancy alter the reactivity of the rat uterine vasculature. Hum Reprod 15: 2496‐2503, 2000.
 42.D'Angelo G, Osol G. Regional variation in resistance artery diameter responses to alpha‐adrenergic stimulation during pregnancy. Am J Phys 264: H78‐H85, 1993.
 43.Danielson LA, Sherwood OD, Conrad KP. Relaxin is a potent renal vasodilator in conscious rats. J Clin Invest 103: 525‐533, 1999.
 44.Davis GL. Hemostatic changes associated with normal and abnormal pregnancies. Clin Lab Sci 13: 223‐228, 2000.
 45.Debrah DO, Novak J, Matthews JE, Ramirez RJ, Shroff SG, Conrad KP. Relaxin is essential for systemic vasodilation and increased global arterial compliance during early pregnancy in conscious rats. Endocrinology 147: 5126‐5131, 2006.
 46.Deligdisch L. Hormonal pathology of the endometrium. Mod Pathol 13: 285‐294, 2000.
 47.D'Errico JN, Doherty C, Fournier SB, Renkel N, Kallontzi S, Goedken M, Fabris L, Buckley B, Stapleton PA. Identification and quantification of gold engineered nanomaterials and impaired fluid transfer across the rat placenta via ex vivo perfusion. Biomed Pharmacother 117: 109148, 2019.
 48.D'Errico JN, Fournier SB, Stapleton PA. Ex vivo perfusion of the rodent placenta. J Vis Exp, 30(147), 2019. DOI: 10.3791/59412.
 49.D'Errico JN, Stapleton PA. Developmental onset of cardiovascular disease ‐ could the proof be in the placenta? Microcirculation 26(8): e12526, 2018.
 50.Downes KL, Grantz KL, Shenassa ED. Maternal, labor, delivery, and perinatal outcomes associated with placental abruption: A systematic review. Am J Perinatol 34: 935‐957, 2017.
 51.Dschietzig T, Bartsch C, Richter C, Laule M, Baumann G, Stangl K. Relaxin, a pregnancy hormone, is a functional endothelin‐1 antagonist: Attenuation of endothelin‐1‐mediated vasoconstriction by stimulation of endothelin type‐B receptor expression via ERK‐1/2 and nuclear factor‐kappaB. Circ Res 92: 32‐40, 2003.
 52.El‐Azzamy H, Dambaeva SV, Katukurundage D, Salazar Garcia MD, Skariah A, Hussein Y, Germain A, Fernandez E, Gilman‐Sachs A, Beaman KD, Kwak‐Kim J. Dysregulated uterine natural killer cells and vascular remodeling in women with recurrent pregnancy losses. Am J Reprod Immunol 80: e13024, 2018.
 53.Espinoza J, Romero R, Mee Kim Y, Kusanovic JP, Hassan S, Erez O, Gotsch F, Than NG, Papp Z, Jai KC. Normal and abnormal transformation of the spiral arteries during pregnancy. J Perinat Med 34: 447‐458, 2006.
 54.Favre‐Inhofer A, Carbonnel M, Revaux A, Sandra O, Mougenot V, Bosc R, Gelin V, Rafii A, Hersant B, Vialard F, Chavatte‐Palmer P, Richard C, Ayoubi JM. Critical steps for initiating an animal uterine transplantation model in sheep: Experience from a case series. Int J Surg 60: 245‐251, 2018.
 55.Ferenczy A, Bertrand G, Gelfand MM. Proliferation kinetics of human endometrium during the normal menstrual cycle. Am J Obstet Gynecol 133: 859‐867, 1979.
 56.Ferretti C, Bruni L, Dangles‐Marie V, Pecking AP, Bellet D. Molecular circuits shared by placental and cancer cells, and their implications in the proliferative, invasive and migratory capacities of trophoblasts. Hum Reprod Update 13: 121‐141, 2007.
 57.Finn CA. Why do women menstruate? Historical and evolutionary review. Eur J Obstet Gynecol Reprod Biol 70: 3‐8, 1996.
 58.Ford SP. Control of uterine and ovarian blood flow throughout the estrous cycle and pregnancy of ewes, sows and cows. J Anim Sci 55 (Suppl 2): 32‐42, 1982.
 59.Fournier SB, Kallontzi S, Fabris L, Love C, Stapleton PA. Effect of gestational age on maternofetal vascular function following single maternal engineered nanoparticle exposure. Cardiovasc Toxicol 19(4): 321‐333, 2019.
 60.Fujitani S, Baldisseri MR. Hemodynamic assessment in a pregnant and peripartum patient. Crit Care Med 33: S354‐S361, 2005.
 61.Fuller R, Barron C, Mandala M, Gokina N, Osol G. Predominance of local over systemic factors in uterine arterial remodeling during pregnancy. Reprod Sci (Thousand Oaks, Calif) 16: 489‐500, 2009.
 62.Fuller R, Colton I, Gokina N, Mandala M, Osol G. Local versus systemic influences on uterine vascular reactivity during pregnancy in the single‐horn gravid rat. Reprod Sci 18: 723‐729, 2011.
 63.Furukawa S, Kuroda Y, Sugiyama A. A comparison of the histological structure of the placenta in experimental animals. J Toxicol Pathol 27: 11‐18, 2014.
 64.Gambino LS, Wreford NG, Bertram JF, Dockery P, Lederman F, Rogers PA. Angiogenesis occurs by vessel elongation in proliferative phase human endometrium. Hum Reprod 17: 1199‐1206, 2002.
 65.Gant NF, Whalley PJ, Everett RB, Worley RJ, MacDonald PC. Control of vascular reactivity in pregnancy. Am J Kidney Dis 9: 303‐307, 1987.
 66.Garcia‐Enguidanos A, Calle ME, Valero J, Luna S, Dominguez‐Rojas V. Risk factors in miscarriage: A review. Eur J Obstet Gynecol Reprod Biol 102: 111‐119, 2002.
 67.Gellersen B, Brosens IA, Brosens JJ. Decidualization of the human endometrium: Mechanisms, functions, and clinical perspectives. Semin Reprod Med 25: 445‐453, 2007.
 68.Gibb AA, Hill BG. Metabolic coordination of physiological and pathological cardiac remodeling. Circ Res 123: 107‐128, 2018.
 69.Gibbons GH, Dzau VJ. The emerging concept of vascular remodeling. N Engl J Med 330: 1431‐1438, 1994.
 70.Girling JE, Rogers PA. Recent advances in endometrial angiogenesis research. Angiogenesis 8: 89‐99, 2005.
 71.Girling JE, Rogers PA. Regulation of endometrial vascular remodelling: Role of the vascular endothelial growth factor family and the angiopoietin‐TIE signalling system. Reproduction 138: 883‐893, 2009.
 72.Glasser SP, Arnett DK, McVeigh GE, Finkelstein SM, Bank AJ, Morgan DJ, Cohn JN. Vascular compliance and cardiovascular disease: A risk factor or a marker? Am J Hypertens 10: 1175‐1189, 1997.
 73.Goeden N, Bonnin A. Ex vivo perfusion of mid‐to‐late‐gestation mouse placenta for maternal‐fetal interaction studies during pregnancy. Nat Protoc 8: 66‐74, 2013.
 74.Gokina NI, Kuzina OY, Fuller R, Osol G. Local uteroplacental influences are responsible for the induction of uterine artery myogenic tone during rat pregnancy. Reprod Sci 16: 1072‐1081, 2009.
 75.Goldman S, Shalev E. Difference in progesterone‐receptor isoforms ratio between early and late first‐trimester human trophoblast is associated with differential cell invasion and matrix metalloproteinase 2 expression. Biol Reprod 74: 13‐22, 2006.
 76.Grafmueller S, Manser P, Diener L, Diener PA, Maeder‐Althaus X, Maurizi L, Jochum W, Krug HF, Buerki‐Thurnherr T, von Mandach U, Wick P. Bidirectional transfer study of polystyrene nanoparticles across the placental barrier in an ex vivo human placental perfusion model. Environ Health Perspect 123: 1280‐1286, 2015.
 77.Greiss FC Jr. Differential reactivity of the myoendometrial and placental vasculatures: Vasodilatation. Am J Obstet Gynecol 111: 611‐625, 1971.
 78.Greiss FC Jr, Anderson SG. Uterine vascular changes during the ovarian cycle. Am J Obstet Gynecol 103: 629‐640, 1969.
 79.Greiss FC Jr, Anderson SG. Effect of ovarian hormones on the uterine vascular bed. Am J Obstet Gynecol 107: 829‐836, 1970.
 80.Greiss FC Jr, Anderson SG, King LC. Uterine vascular bed: Effects of acute hypoxia. Am J Obstet Gynecol 113: 1057‐1064, 1972.
 81.Greiss FC Jr, Anderson SG, Still JG. Uterine pressure‐flow relationships during early gestation. Am J Obstet Gynecol 126: 799‐808, 1976.
 82.Greiss FC Jr, Marston EL. The uterine vascular bed: Effect of estrogens during ovine pregnancy. Am J Obstet Gynecol 93: 720‐722, 1965.
 83.Griendling KK, Fuller EO, Cox RH. Pregnancy‐induced changes in sheep uterine and carotid arteries. Am J Phys 248: H658‐H665, 1985.
 84.Grixti S, Magri CJ, Xuereb R, Fava S. Peripartum cardiomyopathy. Br J Hosp Med (London, England : 2005) 76: 95‐100, 2015.
 85.Gyselaers W, Mullens W, Tomsin K, Mesens T, Peeters L. Role of dysfunctional maternal venous hemodynamics in the pathophysiology of pre‐eclampsia: A review. Ultrasound Obstet Gynecol 38: 123‐129, 2011.
 86.Hafez SA, Borowicz P, Reynolds LP, Redmer DA. Maternal and fetal microvasculature in sheep placenta at several stages of gestation. J Anat 216: 292‐300, 2010.
 87.Halpern W, Osol G, Coy GS. Mechanical behavior of pressurized in vitro prearteriolar vessels determined with a video system. Ann Biomed Eng 12: 463‐479, 1984.
 88.Hanna J, Goldman‐Wohl D, Hamani Y, Avraham I, Greenfield C, Natanson‐Yaron S, Prus D, Cohen‐Daniel L, Arnon TI, Manaster I, Gazit R, Yutkin V, Benharroch D, Porgador A, Keshet E, Yagel S, Mandelboim O. Decidual NK cells regulate key developmental processes at the human fetal‐maternal interface. Nat Med 12: 1065‐1074, 2006.
 89.Hazan AD, Smith SD, Jones RL, Whittle W, Lye SJ, Dunk CE. Vascular‐leukocyte interactions: Mechanisms of human decidual spiral artery remodeling in vitro. Am J Pathol 177: 1017‐1030, 2010.
 90.Hees H, Moll W, Wrobel KH, Hees I. Pregnancy‐induced structural changes and trophoblastic invasion in the segmental mesometrial arteries of the guinea pig (Cavia porcellus L.). Placenta 8: 609‐626, 1987.
 91.Helmo FR, Lopes AMM, Carneiro A, Campos CG, Silva PB, Dos Reis Monteiro MLG, Rocha LP, Dos Reis MA, Etchebehere RM, Machado JR, Correa RRM. Angiogenic and antiangiogenic factors in preeclampsia. Pathol Res Pract 214: 7‐14, 2018.
 92.Hermsteiner M, Zoltan DR, Kunzel W. The vasoconstrictor response of uterine and mesenteric resistance arteries is differentially altered in the course of pregnancy. Eur J Obstet Gynecol Reprod Biol 100: 29‐35, 2001.
 93.Hickey M, Fraser IS. The structure of endometrial microvessels. Hum Reprod 15 (Suppl 3): 57‐66, 2000.
 94.Hilgers RH, Bergaya S, Schiffers PM, Meneton P, Boulanger CM, Henrion D, Levy BI, De Mey JG. Uterine artery structural and functional changes during pregnancy in tissue kallikrein‐deficient mice. Arterioscler Thromb Vasc Biol 23: 1826‐1832, 2003.
 95.Huppertz B, Weiss G, Moser G. Trophoblast invasion and oxygenation of the placenta: Measurements versus presumptions. J Reprod Immunol 101‐102: 74‐79, 2014.
 96.Hutchison SJ, Sudhir K, Chou TM, Chatterjee K. Sex hormones and vascular reactivity. Herz 22: 141‐150, 1997.
 97.Jabbour HN, Kelly RW, Fraser HM, Critchley HO. Endocrine regulation of menstruation. Endocr Rev 27: 17‐46, 2006.
 98.Jacob M, Chappell D, Becker BF. Regulation of blood flow and volume exchange across the microcirculation. Crit Care 20: 319, 2016.
 99.Jauniaux E, Collins S, Burton GJ. Placenta accreta spectrum: Pathophysiology and evidence‐based anatomy for prenatal ultrasound imaging. Am J Obstet Gynecol 218: 75‐87, 2018.
 100.Jelinic M, Marshall SA, Leo CH, Parry LJ, Tare M. From pregnancy to cardiovascular disease: Lessons from relaxin‐deficient animals to understand relaxin actions in the vascular system. Microcirculation 26: e12464, 2019.
 101.Jeyabalan A, Novak J, Danielson LA, Kerchner LJ, Opett SL, Conrad KP. Essential role for vascular gelatinase activity in relaxin‐induced renal vasodilation, hyperfiltration, and reduced myogenic reactivity of small arteries. Circ Res 93: 1249‐1257, 2003.
 102.Ji L, Brkic J, Liu M, Fu G, Peng C, Wang YL. Placental trophoblast cell differentiation: Physiological regulation and pathological relevance to preeclampsia. Mol Asp Med 34: 981‐1023, 2013.
 103.Kelly B, Stone S, Poston L. Cardiovascular adaptation topregnancy: The role of altered vascular structure. Fetal Matern Med Rev 11: 105‐116, 1999.
 104.Keyes LE, Majack R, Dempsey EC, Moore LG. Pregnancy stimulation of DNA synthesis and uterine blood flow in the guinea pig. Pediatr Res 41: 708‐715, 1997.
 105.Kigata T, Shibata H. Ramification pattern of the arteries supplying the rabbit female genital organs. Anat Rec (Hoboken) 303: 1478‐1488, 2020.
 106.Kim M, Park HJ, Seol JW, Jang JY, Cho Y‐S, Kim KR, Choi Y, Lydon JP, Demayo FJ, Shibuya M, Ferrara N, Sung H‐K, Nagy A, Alitalo K, Koh GY. VEGF‐A regulated by progesterone governs uterine angiogenesis and vascular remodelling during pregnancy. EMBO Mol Med 5: 1415‐1430, 2013.
 107.Kimber SJ, Spanswick C. Blastocyst implantation: The adhesion cascade. Semin Cell Dev Biol 11: 77‐92, 2000.
 108.Kypreos KE, Zafirovic S, Petropoulou PI, Bjelogrlic P, Resanovic I, Traish A, Isenovic ER. Regulation of endothelial nitric oxide synthase and high‐density lipoprotein quality by estradiol in cardiovascular pathology. J Cardiovasc Pharmacol Ther 19: 256‐268, 2014.
 109.Lang U, Baker RS, Braems G, Zygmunt M, Kunzel W, Clark KE. Uterine blood flow—a determinant of fetal growth. Eur J Obstet Gynecol Reprod Biol 110 (Suppl 1): S55‐S61, 2003.
 110.Langenbach R, Loftin C, Lee C, Tiano H. Cyclooxygenase knockout mice: Models for elucidating isoform‐specific functions. Biochem Pharmacol 58: 1237‐1246, 1999.
 111.Langer B, Barthelmebs M, Grima M, Coquard C, Imbs JL. In vitro vascular reactivity of the rat utero‐feto‐placental unit. Obstet Gynecol 82: 380‐386, 1993.
 112.Lash GE. Molecular cross‐talk at the feto‐maternal interface. Cold Spring Harb Perspect Med 5: a023010, 2015.
 113.Lash GE, Pitman H, Morgan HL, Innes BA, Agwu CN, Bulmer JN. Decidual macrophages: Key regulators of vascular remodeling in human pregnancy. J Leukoc Biol 100: 315‐325, 2016.
 114.Leduc L, Wasserstrum N, Spillman T, Cotton DB. Baroreflex function in normal pregnancy. Am J Obstet Gynecol 165: 886‐890, 1991.
 115.Leo CH, Jelinic M, Ng HH, Marshall SA, Novak J, Tare M, Conrad KP, Parry LJ. Vascular actions of relaxin: Nitric oxide and beyond. Br J Pharmacol 174: 1002‐1014, 2017.
 116.Leonard S, Lima PD, Croy BA, Murrant CL. Gestational modification of murine spiral arteries does not reduce their drug‐induced vasoconstrictive responses in vivo. Biol Reprod 89: 139, 2013.
 117.Li J, Umar S, Amjedi M, Iorga A, Sharma S, Nadadur RD, Regitz‐Zagrosek V, Eghbali M. New frontiers in heart hypertrophy during pregnancy. Am J Cardiovasc Dis 2: 192‐207, 2012.
 118.Lian X, Beer‐Hammer S, Konig GM, Kostenis E, Nurnberg B, Gollasch M. RXFP1 receptor activation by relaxin‐2 induces vascular relaxation in mice via a galphai2‐protein/PI3Kss/gamma/nitric oxide‐coupled pathway. Front Physiol 9: 1234, 2018.
 119.Liao WX, Magness RR, Chen DB. Expression of estrogen receptors‐alpha and ‐beta in the pregnant ovine uterine artery endothelial cells in vivo and in vitro. Biol Reprod 72: 530‐537, 2005.
 120.Lockwood CJ. Mechanisms of normal and abnormal endometrial bleeding. Menopause 18: 408‐411, 2011.
 121.Ma W, Tan J, Matsumoto H, Robert B, Abrahamson DR, Das SK, Dey SK. Adult tissue angiogenesis: Evidence for negative regulation by estrogen in the uterus. Mol Endocrinol (Baltimore, Md) 15: 1983‐1992, 2001.
 122.Magness RR, Cox K, Rosenfeld CR, Gant NF. Angiotensin II metabolic clearance rate and pressor responses in nonpregnant and pregnant women. Am J Obstet Gynecol 171: 668‐679, 1994.
 123.Magness RR, Phernetton TM, Zheng J. Systemic and uterine blood flow distribution during prolonged infusion of 17beta‐estradiol. Am J Phys 275: H731‐H743, 1998.
 124.Magness RR, Rosenfeld CR. Local and systemic estradiol‐17 beta: Effects on uterine and systemic vasodilation. Am J Phys 256: E536‐E542, 1989.
 125.Magness RR, Rosenfeld CR, Carr BR. Protein kinase C in uterine and systemic arteries during ovarian cycle and pregnancy. Am J Phys 260: E464‐E470, 1991.
 126.Magness RR, Sullivan JA, Li Y, Phernetton TM, Bird IM. Endothelial vasodilator production by uterine and systemic arteries. VI. Ovarian and pregnancy effects on eNOS and NO(x). Am J Physiol Heart Circ Physiol 280: H1692‐H1698, 2001.
 127.Mandalà M. Influence of estrogens on uterine vascular adaptation in normal and preeclamptic pregnancies. Int J Mol Sci 21(7): 2592, 2020.
 128.Mandala M, Gokina N, Osol G. Contribution of nonendothelial nitric oxide to altered rat uterine resistance artery serotonin reactivity during pregnancy. Am J Obstet Gynecol 187: 463‐468, 2002.
 129.Mandala M, Osol G. Physiological remodelling of the maternal uterine circulation during pregnancy. Basic Clin Pharmacol Toxicol 110: 12‐18, 2012.
 130.Markee JE. Menstruation in intraocular endometrial transplants in the Rhesus monkey. Am J Obstet Gynecol 131: 558‐559, 1978.
 131.Marsh MM, Malakooti N, Taylor NH, Findlay JK, Salamonsen LA. Endothelin and neutral endopeptidase in the endometrium of women with menorrhagia. Hum Reprod 12: 2036‐2040, 1997.
 132.Marshall SA, Senadheera SN, Jelinic M, O'Sullivan K, Parry LJ, Tare M. Relaxin deficiency leads to uterine artery dysfunction during pregnancy in mice. Front Physiol 9: 255, 2018.
 133.Marshall SA, Senadheera SN, Parry LJ, Girling JE. The role of relaxin in normal and abnormal uterine function during the menstrual cycle and early pregnancy. Reprod Sci 24: 342‐354, 2017.
 134.Mateev SN, Mouser R, Young DA, Mecham RP, Moore LG. Chronic hypoxia augments uterine artery distensibility and alters the circumferential wall stress‐strain relationship during pregnancy. J Appl Physiol (1985) 100: 1842‐1850, 2006.
 135.Maybin JA, Critchley HO. Menstrual physiology: Implications for endometrial pathology and beyond. Hum Reprod Update 21: 748‐761, 2015.
 136.Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP, Karumanchi SA. Excess placental soluble fms‐like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 111: 649‐658, 2003.
 137.McCarron JG, Lee MD, Wilson C. The endothelium solves problems that endothelial cells do not know exist. Trends Pharmacol Sci 38: 322‐338, 2017.
 138.McGuane JT, Danielson LA, Debrah JE, Rubin JP, Novak J, Conrad KP. Angiogenic growth factors are new and essential players in the sustained relaxin vasodilatory pathway in rodents and humans. Hypertension 57: 1151‐1160, 2011.
 139.Mendelson CR. Minireview: Fetal‐maternal hormonal signaling in pregnancy and labor. Mol Endocrinol 23: 947‐954, 2009.
 140.Merchant SJ, Davidge ST. The role of matrix metalloproteinases in vascular function: Implications for normal pregnancy and pre‐eclampsia. BJOG 111: 931‐939, 2004.
 141.Messinis IE. Ovarian feedback, mechanism of action and possible clinical implications. Hum Reprod Update 12: 557‐571, 2006.
 142.Miller VM, Duckles SP. Vascular actions of estrogens: Functional implications. Pharmacol Rev 60: 210‐241, 2008.
 143.Miller VM, Mulvagh SL. Sex steroids and endothelial function: Translating basic science to clinical practice. Trends Pharmacol Sci 28: 263‐270, 2007.
 144.Mitro SD, Sanchez SE, Palomino H, Gelaye B, Williams MA. Childhood abuse, intimate partner violence, and placental abruption among Peruvian women. Ann Epidemiol, 2018.
 145.Modena MG. “Estrogens and the heart: Do they help or hurt?” How estrogen impacts the cardiovascular system. SOJ Gynecol Obstet Womens Health 2(1): 8, 2016.
 146.Moisey DM, Tulenko T. Increased sensitivity to angiotensin in uterine arteries from pregnant rabbits. Am J Phys 244: H335‐H340, 1983.
 147.Moser G, Windsperger K, Pollheimer J, de Sousa Lopes SC, Huppertz B. Human trophoblast invasion: New and unexpected routes and functions. Histochem Cell Biol 150: 361‐370, 2018.
 148.Mu J, Adamson SL. Developmental changes in hemodynamics of uterine artery, utero‐ and umbilicoplacental, and vitelline circulations in mouse throughout gestation. Am J Physiol Heart Circ Physiol 291: H1421‐H1428, 2006.
 149.Mulvany MJ. Vascular remodelling of resistance vessels: Can we define this? Cardiovasc Res 41: 9‐13, 1999.
 150.Murakami K, Kuroda K, Brosens JJ. Treatment Strategy for Unexplained Infertility and Recurrent Miscarriage. Singapore: Springer, 2018, p. 125.
 151.Nagy JA, Dvorak AM, Dvorak HF. VEGF‐A and the induction of pathological angiogenesis. Annu Rev Pathol 2: 251‐275, 2007.
 152.Nisell H, Hjemdahl P, Linde B. Cardiovascular responses to circulating catecholamines in normal pregnancy and in pregnancy‐induced hypertension. Clin Physiol 5: 479‐493, 1985.
 153.Novak J, Parry LJ, Matthews JE, Kerchner LJ, Indovina K, Hanley‐Yanez K, Doty KD, Debrah DO, Shroff SG, Conrad KP. Evidence for local relaxin ligand‐receptor expression and function in arteries. FASEB J 20: 2352‐2362, 2006.
 154.Ochoa‐Bernal MA, Fazleabas AT. Physiologic events of embryo implantation and decidualization in human and non‐human primates. Int J Mol Sci 21(6): 1973, 2020.
 155.Okada H, Tsuzuki T, Murata H. Decidualization of the human endometrium. Reprod Med Biol 17: 220‐227, 2018.
 156.Orshal JM, Khalil RA. Gender, sex hormones, and vascular tone. Am J Phys Regul Integr Comp Phys 286: R233‐R249, 2004.
 157.Osol G, Barron C, Gokina N, Mandala M. Inhibition of nitric oxide synthases abrogates pregnancy‐induced uterine vascular expansive remodeling. J Vasc Res 46: 478‐486, 2009.
 158.Osol G, Cipolla M. Interaction of myogenic and adrenergic mechanisms in isolated, pressurized uterine radial arteries from late‐pregnant and nonpregnant rats. Am J Obstet Gynecol 168: 697‐705, 1993.
 159.Osol G, Cipolla M. Pregnancy‐induced changes in the three‐dimensional mechanical properties of pressurized rat uteroplacental (radial) arteries. Am J Obstet Gynecol 168: 268‐274, 1993.
 160.Osol G, Ko NL, Mandala M. Plasticity of the maternal vasculature during pregnancy. Annu Rev Physiol 81: 89‐111, 2019.
 161.Osol G, Mandala M. Maternal uterine vascular remodeling during pregnancy. Physiology (Bethesda) 24: 58‐71, 2009.
 162.Osol G, Moore LG. Maternal uterine vascular remodeling during pregnancy. Microcirculation 21: 38‐47, 2014.
 163.Oyelese Y, Smulian JC. Placenta previa, placenta accreta, and vasa previa. Obstet Gynecol 107: 927‐941, 2006.
 164.Page KL, Celia G, Leddy G, Taatjes DJ, Osol G. Structural remodeling of rat uterine veins in pregnancy. Am J Obstet Gynecol 187: 1647‐1652, 2002.
 165.Paller MS. Mechanism of decreased pressor responsiveness to ANG II, NE, and vasopressin in pregnant rats. Am J Phys 247: H100‐H108, 1984.
 166.Palmer SK, Zamudio S, Coffin C, Parker S, Stamm E, Moore LG. Quantitative estimation of human uterine artery blood flow and pelvic blood flow redistribution in pregnancy. Obstet Gynecol 80: 1000‐1006, 1992.
 167.Parry LJ, Vodstrcil LA. Relaxin physiology in the female reproductive tract during pregnancy. Adv Exp Med Biol 612: 34‐48, 2007.
 168.Pastore MB, Jobe SO, Ramadoss J, Magness RR. Estrogen receptor‐alpha and estrogen receptor‐beta in the uterine vascular endothelium during pregnancy: Functional implications for regulating uterine blood flow. Semin Reprod Med 30: 46‐61, 2012.
 169.Phipps E, Prasanna D, Brima W, Jim B. Preeclampsia: Updates in pathogenesis, definitions, and guidelines. Clin J Am Soc Nephrol 11: 1102‐1113, 2016.
 170.Rana S, Lemoine E, Granger JP, Karumanchi SA. Preeclampsia: Pathophysiology, challenges, and perspectives. Circ Res 124: 1094‐1112, 2019.
 171.Raz T, Avni R, Addadi Y, Cohen Y, Jaffa AJ, Hemmings B, Garbow JR, Neeman M. The hemodynamic basis for positional‐ and inter‐fetal dependent effects in dual arterial supply of mouse pregnancies. PLoS One 7: e52273, 2012.
 172.Red‐Horse K, Kapidzic M, Zhou Y, Feng KT, Singh H, Fisher SJ. EPHB4 regulates chemokine‐evoked trophoblast responses: A mechanism for incorporating the human placenta into the maternal circulation. Development 132: 4097‐4106, 2005.
 173.Renaud SJ, Scott RL, Chakraborty D, Rumi MA, Soares MJ. Natural killer‐cell deficiency alters placental development in rats. Biol Reprod 96: 145‐158, 2017.
 174.Resnik R, Brink GW, Plumer MH. The effect of progesterone on estrogen‐induced uterine blood flow. Am J Obstet Gynecol 128: 251‐254, 1977.
 175.Reyes LM, Usselman CW, Davenport MH, Steinback CD. Sympathetic nervous system regulation in human normotensive and hypertensive pregnancies. Hypertension 71: 793‐803, 2018.
 176.Rhee TK, Ryu RK, Bangash AK, Wang D, Szolc‐Kowalska B, Harris KR, Sato KT, Chrisman HB, Vogelzang RL, Paunesku T, Woloschak GE, Larson AC, Omary RA. Rabbit VX2 tumors as an animal model of uterine fibroids and for uterine artery embolization. J Vasc Interv Radiol 18: 411‐418, 2007.
 177.Roberts JM. Pathophysiology of ischemic placental disease. Semin Perinatol 38: 139‐145, 2014.
 178.Robertshaw I, Bian F, Das SK. Mechanisms of uterine estrogen signaling during early pregnancy in mice: An update. J Mol Endocrinol 56: R127‐R138, 2016.
 179.Robson A, Harris LK, Innes BA, Lash GE, Aljunaidy MM, Aplin JD, Baker PN, Robson SC, Bulmer JN. Uterine natural killer cells initiate spiral artery remodeling in human pregnancy. FASEB J 26: 4876‐4885, 2012.
 180.Rogers MS, Rohan RM, Birsner AE, D'Amato RJ. Genetic loci that control vascular endothelial growth factor‐induced angiogenesis. FASEB J 17: 2112‐2114, 2003.
 181.Rogers PA, Abberton KM. Endometrial arteriogenesis: Vascular smooth muscle cell proliferation and differentiation during the menstrual cycle and changes associated with endometrial bleeding disorders. Microsc Res Tech 60: 412‐419, 2003.
 182.Romero R, Espinoza J, Goncalves LF, Kusanovic JP, Friel LA, Nien JK. Inflammation in preterm and term labour and delivery. Semin Fetal Neonatal Med 11: 317‐326, 2006.
 183.Rosenfeld CR, Cox BE, Roy T, Magness RR. Nitric oxide contributes to estrogen‐induced vasodilation of the ovine uterine circulation. J Clin Invest 98: 2158‐2166, 1996.
 184.Rosenfeld CR, DeSpain K, Liu XT. Defining the differential sensitivity to norepinephrine and angiotensin II in the ovine uterine vasculature. Am J Phys Regul Integr Comp Phys 302: R59‐R67, 2012.
 185.Rosenfeld CR, DeSpain K, Word RA, Liu XT. Differential sensitivity to angiotensin II and norepinephrine in human uterine arteries. J Clin Endocrinol Metab 97: 138‐147, 2012.
 186.Rosenfeld CR, Roy T, Cox BE. Mechanisms modulating estrogen‐induced uterine vasodilation. Vasc Pharmacol 38: 115‐125, 2002.
 187.Ross RL, Serock MR, Khalil RA. Experimental benefits of sex hormones on vascular function and the outcome of hormone therapy in cardiovascular disease. Curr Cardiol Rev 4: 309‐322, 2008.
 188.Rupnow HL, Phernetton TM, Shaw CE, Modrick ML, Bird IM, Magness RR. Endothelial vasodilator production by uterine and systemic arteries. VII. Estrogen and progesterone effects on eNOS. Am J Physiol Heart Circ Physiol 280: H1699‐H1705, 2001.
 189.Saha PR, Alsip NL, Henzel MK, Asher EF. Role of nitric oxide and cyclooxygenase products in controlling vascular tone in uterine microvessels of rats. J Reprod Fertil 112: 211‐216, 1998.
 190.Salmani D, Purushothaman S, Somashekara SC, Gnanagurudasan E, Sumangaladevi K, Harikishan R, Venkateshwarareddy M. Study of structural changes in placenta in pregnancy‐induced hypertension. J Nat Sc Biol Med 5: 352‐355, 2014.
 191.Sampaolesi M, Van Calsteren K. Physiological and pathological gestational cardiac hypertrophy: What can we learn from rodents? Cardiovasc Res 113: 1533‐1535, 2017.
 192.Sandoo A, van Zanten JJ, Metsios GS, Carroll D, Kitas GD. The endothelium and its role in regulating vascular tone. Open Cardiovasc Med J 4: 302‐312, 2010.
 193.Sanghavi M, Rutherford JD. Cardiovascular physiology of pregnancy. Circulation 130: 1003‐1008, 2014.
 194.Santos R, Silva F, Faustino Ribeiro R, Stefanon I. Sex hormones in the cardiovascular system. Horm Mol Biol Clin Invest 18(2): 89‐103, 2014.
 195.Scantlebury DC, Hayes SN, Garovic VD. Pre‐eclampsia and maternal placental syndromes: An indicator or cause of long‐term cardiovascular disease? Heart 98: 1109‐1111, 2012.
 196.Schmidt P, Raines DA. Placental abruption (abruptio placentae). In: StatPearls. Treasure Island (FL): StatPearls Publishing LLC., 2018.
 197.Sharma S, Godbole G, Modi D. Decidual control of trophoblast invasion. Am J Reprod Immunol 75: 341‐350, 2016.
 198.Silver RM, Branch DW. Placenta accreta spectrum. N Engl J Med 378: 1529‐1536, 2018.
 199.Skipor J, Kowalik A, Stefańczyk‐Krzymowska S. Luteinising hormone attenuates the vascular response to norepinephrine. Acta Vet Hung 55: 251‐257, 2007.
 200.Sladek SM, Magness RR, Conrad KP. Nitric oxide and pregnancy. Am J Phys 272: R441‐R463, 1997.
 201.Smith SD, Dunk CE, Aplin JD, Harris LK, Jones RL. Evidence for immune cell involvement in decidual spiral arteriole remodeling in early human pregnancy. Am J Pathol 174: 1959‐1971, 2009.
 202.Soares MJ, Chakraborty D, Kubota K, Renaud SJ, Rumi MA. Adaptive mechanisms controlling uterine spiral artery remodeling during the establishment of pregnancy. Int J Dev Biol 58: 247‐259, 2014.
 203.Soares MJ, Varberg KM, Iqbal K. Hemochorial placentation: Development, function, and adaptations. Biol Reprod 99: 196‐211, 2018.
 204.Soma‐Pillay P, Nelson‐Piercy C, Tolppanen H, Mebazaa A. Physiological changes in pregnancy. Cardiovasc J Afr 27: 89‐94, 2016.
 205.Sood R, Kalloway S, Mast AE, Hillard CJ, Weiler H. Fetomaternal cross talk in the placental vascular bed: Control of coagulation by trophoblast cells. Blood 107: 3173‐3180, 2006.
 206.Sprague BJ, Phernetton TM, Magness RR, Chesler NC. The effects of the ovarian cycle and pregnancy on uterine vascular impedance and uterine artery mechanics. Eur J Obstet Gynecol Reprod Biol 144 (Suppl 1): S170‐S178, 2009.
 207.Stapleton PA, McBride CR, Yi J, Abukabda AB, Nurkiewicz TR. Estrous cycle‐dependent modulation of in vivo microvascular dysfunction after nanomaterial inhalation. Reprod Toxicol 78: 20‐28, 2018.
 208.Stapleton PA, McBride CR, Yi J, Nurkiewicz TR. Uterine microvascular sensitivity to nanomaterial inhalation: An in vivo assessment. Toxicol Appl Pharmacol 288: 420‐428, 2015.
 209.Taysi S, Tascan AS, Ugur MG, Demir M. Radicals, oxidative/nitrosative stress and preeclampsia. Mini Rev Med Chem 19: 178‐193, 2019.
 210.Thaler I, Manor D, Itskovitz J, Rottem S, Levit N, Timor‐Tritsch I, Brandes JM. Changes in uterine blood flow during human pregnancy. Am J Obstet Gynecol 162: 121‐125, 1990.
 211.Thornburg KL, Jacobson S‐L, Giraud GD, Morton MJ. Hemodynamic changes in pregnancy. Semin Perinatol 24: 11‐14, 2000.
 212.Thornton P, Douglas J. Coagulation in pregnancy. Best Pract Res Clin Obstet Gynaecol 24: 339‐352, 2010.
 213.Tkachenko O, Shchekochikhin D, Schrier RW. Hormones and hemodynamics in pregnancy. Int J Endocrinol Metab 12: e14098, 2014.
 214.Toda N, Toda H, Okamura T. Regulation of myometrial circulation and uterine vascular tone by constitutive nitric oxide. Eur J Pharmacol 714: 414‐423, 2013.
 215.Van Buren GA, Yang DS, Clark KE. Estrogen‐induced uterine vasodilatation is antagonized by L‐nitroarginine methyl ester, an inhibitor of nitric oxide synthesis. Am J Obstet Gynecol 167: 828‐833, 1992.
 216.Van Dreden P, Woodhams B, Rousseau A, Favier M, Favier R. Comparative evaluation of tissue factor and thrombomodulin activity changes during normal and idiopathic early and late foetal loss: The cause of hypercoagulability? Thromb Res 129: 787‐792, 2012.
 217.Veerareddy S, Campbell ME, Williams SJ, Baker PN, Davidge ST. Myogenic reactivity is enhanced in rat radial uterine arteries in a model of maternal undernutrition. Am J Obstet Gynecol 191: 334‐339, 2004.
 218.Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim YM, Bdolah Y, Lim KH, Yuan HT, Libermann TA, Stillman IE, Roberts D, D'Amore PA, Epstein FH, Sellke FW, Romero R, Sukhatme VP, Letarte M, Karumanchi SA. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 12: 642‐649, 2006.
 219.Vodstrcil LA, Tare M, Novak J, Dragomir N, Ramirez RJ, Wlodek ME, Conrad KP, Parry LJ. Relaxin mediates uterine artery compliance during pregnancy and increases uterine blood flow. FASEB J 26: 4035‐4044, 2012.
 220.Walter I, Schonkypl S. Extracellular matrix components and matrix degrading enzymes in the feline placenta during gestation. Placenta 27: 291‐306, 2006.
 221.Wang SY, Datta S, Segal S. Pregnancy alters adrenergic mechanisms in uterine arterioles of rats. Anesth Analg 94: 1304‐1309, 2002.
 222.Wang X, Chen C, Wang L, Chen D, Guang W, French J. Conception, early pregnancy loss, and time to clinical pregnancy: A population‐based prospective study. Fertil Steril 79: 577‐584, 2003.
 223.Wang Y, Shuang Z. Chapter 2: Placental blood circulation. In: San Rafael CA, editor. Vascular Biology of the Placenta. Morcan and Claypool Life Sciences, 2010.
 224.Wehrwein E, Orer HS, Barman S. Overview of the anatomy, physiology, and pharmacology of the autonomic nervous system. Compr Physiol 6: 1239‐1278, 2011.
 225.Weiner C, Liu KZ, Thompson L, Herrig J, Chestnut D. Effect of pregnancy on endothelium and smooth muscle: Their role in reduced adrenergic sensitivity. Am J Phys 261: H1275‐H1283, 1991.
 226.Weiner CP, Martinez E, Chestnut DH, Ghodsi A. Effect of pregnancy on uterine and carotid artery response to norepinephrine, epinephrine, and phenylephrine in vessels with documented functional endothelium. Am J Obstet Gynecol 161: 1605‐1610, 1989.
 227.Weiner CP, Thompson LP, Liu KZ, Herrig JE. Endothelium‐derived relaxing factor and indomethacin‐sensitive contracting factor alter arterial contractile responses to thromboxane during pregnancy. Am J Obstet Gynecol 166: 1171‐1178; discussion 1179‐1181, 1992.
 228.Weiner CP, Thompson LP, Van Voorhis BJ. The role of nitric oxide in female reproduction. Fetal Matern Med Rev 7: 175‐205, 1995.
 229.Weiss G, Sundl M, Glasner A, Huppertz B, Moser G. The trophoblast plug during early pregnancy: A deeper insight. Histochem Cell Biol 146: 749‐756, 2016.
 230.Wen L, Chen L‐H, Li H‐Y, Chang S‐P, Liao C‐Y, Tsui K‐H, Sung Y‐J, Chao K‐C. Roles of estrogen and progesterone in endometrial hemodynamics and vascular endothelial growth factor production. J Chin Med Assoc 72: 188‐193, 2009.
 231.Wendel MP, Shnaekel KL, Magann EF. Uterine inversion: A review of a life‐threatening obstetrical emergency. Obstet Gynecol Surv 73: 411‐417, 2018.
 232.White RE. Estrogen and vascular function. Vasc Pharmacol 38: 73‐80, 2002.
 233.Whitley GS, Cartwright JE. Trophoblast‐mediated spiral artery remodelling: A role for apoptosis. J Anat 215: 21‐26, 2009.
 234.Wight E, Kung CF, Moreau P, Takase H, Bersinger NA, Luscher TF. Aging, serum estradiol levels, and pregnancy differentially affect vascular reactivity of the rat uterine artery. J Soc Gynecol Investig 7: 106‐113, 2000.
 235.Wight E, Kung CF, Moreau P, Takase H, Luscher TF. Chronic blockade of nitric oxide synthase and endothelin receptors during pregnancy in the rat: Effect on reactivity of the uterine artery in vitro. J Soc Gynecol Investig 5: 288‐295, 1998.
 236.Williams JW. Regeneration of the uterine mucosa after delivery with especial reference to the placental site. Amer J Obstet Gynec 22: 664‐696, 1931.
 237.Withers SB, Taggart MJ, Baker P, Austin C. Responses of isolated pressurised rat uterine arteries to changes in pressure: Effects of pre‐constriction, endothelium and pregnancy. Placenta 30: 529‐535, 2009.
 238.Xiao D, Huang X, Bae S, Ducsay CA, Zhang L. Cortisol‐mediated potentiation of uterine artery contractility: Effect of pregnancy. Am J Physiol Heart Circ Physiol 283: H238‐H246, 2002.
 239.Xiao D, Liu Y, Pearce WJ, Zhang L. Endothelial nitric oxide release in isolated perfused ovine uterine arteries: Effect of pregnancy. Eur J Pharmacol 367: 223‐230, 1999.
 240.Zhang J, Chen Z, Smith GN, Croy BA. Natural killer cell‐triggered vascular transformation: Maternal care before birth? Cell Mol Immunol 8: 1‐11, 2011.
 241.Zhou Y, Damsky CH, Fisher SJ. Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in this syndrome? J Clin Invest 99: 2152‐2164, 1997.
 242.Zhu J‐Y, Pang Z‐J, Yu Y‐H. Regulation of trophoblast invasion: The role of matrix metalloproteinases. Rev Obstet Gynecol 5: e137‐e143, 2012.
 243.Zia S. Placental location and pregnancy outcome. J Turk Ger Gynecol Assoc 14: 190‐193, 2013.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Sara B. Fournier, Jeanine N. D'Errico, Phoebe A. Stapleton. Uterine Vascular Control Preconception and During Pregnancy. Compr Physiol 2021, 11: 1871-1893. doi: 10.1002/cphy.c190015