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Hypertension: Physiology and Pathophysiology

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Abstract

Despite major advances in understanding the pathophysiology of hypertension and availability of effective and safe antihypertensive drugs, suboptimal blood pressure (BP) control is still the most important risk factor for cardiovascular mortality and is globally responsible for more than 7 million deaths annually. Short‐term and long‐term BP regulation involve the integrated actions of multiple cardiovascular, renal, neural, endocrine, and local tissue control systems. Clinical and experimental observations strongly support a central role for the kidneys in the long‐term regulation of BP, and abnormal renal‐pressure natriuresis is present in all forms of chronic hypertension. Impaired renal‐pressure natriuresis and chronic hypertension can be caused by intrarenal or extrarenal factors that reduce glomerular filtration rate or increase renal tubular reabsorption of salt and water; these factors include excessive activation of the renin‐angiotensin‐aldosterone and sympathetic nervous systems, increased formation of reactive oxygen species, endothelin, and inflammatory cytokines, or decreased synthesis of nitric oxide and various natriuretic factors. In human primary (essential) hypertension, the precise causes of impaired renal function are not completely understood, although excessive weight gain and dietary factors appear to play a major role since hypertension is rare in nonobese hunter‐gathers living in nonindustrialized societies. Recent advances in genetics offer opportunities to discover gene‐environment interactions that may also contribute to hypertension, although success thus far has been limited mainly to identification of rare monogenic forms of hypertension. © 2012 American Physiological Society. Compr Physiol 2:2393‐2442, 2012.

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Figure 1. Figure 1.

Failure of changes in total peripheral vascular resistance (TPR) to cause chronic changes in arterial pressure in several clinical conditions in which the kidneys are functioning normally. In each case, there is a reciprocal relationship between TPR and cardiac output, but no long‐term effect on arterial pressure .

Figure 2. Figure 2.

Time dependency of blood pressure control mechanisms. Approximate maximum feedback gains of various blood pressure control mechanisms at different time intervals after the onset of a disturbance to arterial pressure .

Figure 3. Figure 3.

Block diagram showing the basic elements of the renal‐body fluid feedback mechanism for long‐term regulation of arterial pressure.

Figure 4. Figure 4.

Long‐term effects of increased total peripheral resistance (TPR), such as that caused by closure of a large arteriovenous fistula, with no changes in the renal pressure natriuresis relationship. Blood pressure is initially increased from point A to point B, but elevated blood pressure cannot be sustained because sodium excretion exceeds intake, reducing extracellular fluid volume until blood pressure returns to normal and sodium balance is reestablished .

Figure 5. Figure 5.

Long‐term effects of norepinephrine, a vasoconstrictor that has a relatively weak effect to impair pressure natriuresis. The normal curve (blue) is compared with the vasoconstrictor curve (red line). Initially the vasoconstrictor raises blood pressure (from point A to point B) above the renal set point for sodium balance. However, increased arterial pressure causes a transient natriuresis and decreases extracellular fluid volume until blood pressure eventually stabilizes at a level (point C) at which sodium intake and output are balanced at a reduced extracellular fluid volume .

Figure 6. Figure 6.

Steady‐state relationships between arterial pressure and urinary sodium excretion and sodium intake for subjects with normal kidneys and four general types of renal dysfunction that cause hypertension: decreased kidney mass, increased reabsorption in distal and collecting tubules, reductions in glomerular capillary filtration coefficient (Kf), and increased preglomerular resistance. Note that increased preglomerular resistance causes salt‐insensitive hypertension, whereas the other renal abnormalities cause salt‐sensitive hypertension.

Figure 7. Figure 7.

The effect of reducing kidney mass on salt sensitivity of blood pressure in dogs. Note that as long as sodium chloride intake was normal, surgical reduction of kidney mass by 25% or even 70% did not markedly alter arterial pressure. However, after loss of kidney mass, blood pressure became exquisitely sensitive to high sodium chloride intake .

Figure 8. Figure 8.

Changes in mean arterial pressure during chronic changes in sodium intake in normal control dogs, after angiotensin‐converting enzyme (ACE) inhibition, or after ANG II infusion (5 ng/kg/min) to prevent ANG II from being suppressed when sodium intake was raised .

Figure 9. Figure 9.

Blood pressure (BP) lowering effect of radiofrequency ablation of the renal sympathetic nerves for 18 months (M) in patients who were resistant to the usual antihypertensive drugs. SBP, systolic blood pressure; DBP, diastolic blood pressure .

Figure 10. Figure 10.

Effects of prolonged baroreflex activation by electrical stimulation of carotid sinus nerves on mean arterial pressure and urinary sodium excretion in normal control dogs in dogs that were made hypertensive by infusion of angiotensin II (Ang II) or by feeding a high‐fat diet to produce obesity (Obese). Values for mitogen‐activated protein (MAP) before baroreflex activation: control = 93 ± 1 mm Hg, Ang II hypertension = 129 ± 3 mm Hg, and obese hypertension = 110 ± 3 mm Hg .

Figure 11. Figure 11.

Steady‐state relationships between arterial pressure and sodium intake and excretion under normal conditions with a fully functional RAAS, after blockade of ANG II formation with an angiotensin‐converting enzyme (ACE) inhibitor, and after ANG II infusion at a low dose to prevent ANG II levels from being suppressed when sodium intake was increased. The numbers in parentheses are estimated ANG II levels expressed as times normal .

Figure 12. Figure 12.

Angiotensin (ANG) II increases proximal tubular reabsorption by binding to receptors on the luminal and basolateral membranes and stimulating Na+/H+ antiporter, Na+/HCO3 cotransport, and Na+/K+ adenosine triphosphatase (ATPase) activity. ANG II also increases reabsorption by increasing interstitial fluid colloid osmotic pressure and decreasing interstitial fluid hydrostatic pressure .

Figure 13. Figure 13.

Summary of the pro‐ and antihypertensive actions of endothelin‐1 (ET‐1). The ability of ET‐1 to influence blood pressure and renal pressure natriuresis is highly dependent on where ET‐1 is produced and which renal ET receptor type is activated. ET‐1 can elicit a prohypertensive antinatriuretic effect by activating ETA receptors in the kidneys. Activation of renal ETA receptors increases renal vascular resistance (RVR), which decreases renal plasma flow (RPF) and glomerular filtration rate (GFR), and enhances sodium reabsorption by decreasing peritubular capillary hydrostatic pressure (Pc). The net effect of renal ETA receptor activation is decreased sodium excretion and increased blood pressure. Conversely, ET‐1 can elicit an antihypertensive natriuretic effect via ETB receptor activation. Activation of the renal ETB receptor leads to enhanced synthesis of nitric oxide (NO) and 20‐HETE and suppression of the renin‐angiotensin system. The net effect of renal ETB receptor activation is increased sodium excretion and decreased blood pressure.

Figure 14. Figure 14.

Differences in systolic blood pressure (BP) between collecting duct (CD) endothelin type A and B receptor (ETA/B) KO and control mice on a normal‐ or high‐Na diet .

Figure 15. Figure 15.

Renal mechanisms whereby reduced nitric oxide (NO) synthesis decreases pressure natriuresis and increases blood pressure. Decreased endothelial‐derived nitric oxide (EDNO) synthesis impairs renal sodium excretory function by increasing basal renal vascular resistance, enhancing the renal vascular responsiveness to vasoconstrictors such as ANG II or norepinephrine, or activating the reninangiotensin system. Reductions in NO synthesis also impair sodium excretory function either by directly increasing tubular reabsorption or by altering intrarenal physical factors, such as renal interstitial hydrostatic pressure or medullary blood flow.

Figure 16. Figure 16.

Renal mechanisms whereby reactive oxygen species impair pressure natriuresis and increase blood pressure. An increase in renal oxidative stress impairs renal pressure natriuresis by increasing renal vascular resistance or enhancing tubuloglomerular feedback, both of which decrease the glomerular filtration rate. Renal oxidative stress also reduces sodium excretion by direct effects to increase renal tubular reabsorption.

Figure 17. Figure 17.

Potential mechanisms whereby inhibitors of vascular endothelial growth factor (VEGF) receptor signaling raise blood pressure. Blockade of VEGF receptors results in endothelial dysfunction leading to decreased production of endothelium derived relaxing such as nitric oxide and prostaglandin or enhanced production of vasoconstrictor factors such as thromboxane and endothelin. Inhibitors of VEGF signaling may also result in alterations in glomerular structure and function. These changes may elevate blood pressure by reducing renal blood flow and GFR and impairing the kidney's ability to excrete sodium and water (depicted by a decrease in the pressure natriuresis relationship).

Figure 18. Figure 18.

Proposed role of T cells and inflammation in progression of chronic hypertension. Initial hypertensive stimuli leads to renal injury, neoantigen formation, and eventual T cell activation within the kidney. T‐cell‐derived signals promote entry of other inflammatory cells such as macrophages which result in renal vasoconstriction and sodium reabsorption, thereby increasing the severity of hypertension .

Figure 19. Figure 19.

Summary of the pro‐ and antihypertensive actions of 20‐HETE. 20‐HETE produced in the renal tubules inhibits sodium transport and lowers blood pressure. In the renal vasculature and glomerulus, 20‐HETE is a constrictor that lowers glomerular filtration rate, promotes sodium retention, and increases arterial pressure. In the peripheral circulation, 20‐HETE increases vascular tone and increases blood pressure. TGF, tubuloglomerular feedback; TPR, total peripheral resistance.

Figure 20. Figure 20.

Effect of atrial natriuretic peptide (ANP) receptor knockout on the chronic pressure natriuresis relationship .

Figure 21. Figure 21.

Effect of weight gain to shift the frequency distribution of blood pressure to higher levels. Not all obese subjects have blood pressures in the hypertensive range (> 140/90 mmHg), but excess weight gain raises blood pressure above the baseline level for an individual.

Figure 22. Figure 22.

Summary of mechanisms by which obesity causes hypertension and renal injury. Visceral obesity increases blood pressure by activation of the sympathetic nervous system (SNS), the renin‐angiotensin‐aldosterone system (RAAS), and by physical compression of the kidneys from the fat surrounding the kidneys. SNS activation may be caused by, in part, the effects of leptin, which acts on proopiomelanocortin (POMC) neurons in the hypothalamus and brainstem. Obesity‐induced hypertension and glomerular hyperfiltration may cause renal injury, especially when combined with dyslipidemia and hyperglycemia. Renal injury then exacerbates the hypertension and makes it more difficult to control.

Figure 23. Figure 23.

Possible links among leptin and its effects on the hypothalamus, sympathetic activation, and hypertension. Within the hypothalamus, one of the key pathways of leptin's action on appetite, SNS activity, and blood pressure is stimulation of the proopiomelanocortin (POMC) neurons in the arcuate nucleus (ARC). These neurons send projections to the paraventricular nucleus (PVN) and lateral hypothalamus, releasing α‐melanocyte‐stimulating hormone (α‐MSH), which then acts as an agonist for melanocortin 4 receptors (MC4R). These neurons, in turn, send projections to the nucleus of the solitary tract (NTS) to effect changes in appetite, SNS activity, and blood pressure. Leptin also suppresses the NPY/AGRP neurons, but their role in controlling SNS activity and blood pressure are still unclear. Leptin‐melanocortin activation in distinct areas of the brain and through multiple intracellular signaling pathways may differentially regulate appetite, energy expenditure, and arterial pressure. LH, lateral hypothalamus; RSNA, renal sympathetic nerve activity.

Figure 24. Figure 24.

Changes (Δ) in mean arterial pressure (mmHg), cumulative sodium balance (mmol), and glomerular filtration rate (mL/min) in control, untreated dogs and mineralocorticoid receptor antagonist (eplerenone) treated (10 mg/kg, twice daily) dogs that were fed a high fat diet for 5 weeks to develop obesity .

Figure 25. Figure 25.

Adjusted relative risk for end stage renal disease by body mass index (BMI) in 320,252 subjects. Model adjusted for Multiphasic Health Checkup period, age, sex, race, education level, smoking status, history of myocardial infarction, serum cholesterol level, proteinuria, hematuria, and serum creatinine level. Error bars represent 95% confidence intervals .

Figure 26. Figure 26.

Cardiovascular, metabolic, and renal disease associated with visceral obesity which appears to be a primary cause of all of cluster of CVD risk factors in the metabolic syndrome. CRP, C‐reactive protein; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; PAI, platelet activator inhibitor; PP, postprandial; RAAS, renin‐angiotensin‐aldosterone system; SNS, sympathetic nervous system; TG, triglycerides.

Figure 27. Figure 27.

Effect of placing a constricting clamp on the renal artery of one kidney after removal of the contralateral kidney (one‐kidney, 1‐clip Goldblatt hypertension) .

Figure 28. Figure 28.

Effects of chronic aldosterone infusion when renal perfusion pressure was servo controlled (red lines) or allowed to increase (blue lines). When renal perfusion pressure was prevented from increasing, “escape” from sodium retention did not occur and cumulative sodium balance and systemic arterial pressure continued to increase .

Figure 29. Figure 29.

Mechanisms linking placental ischemia and hypertension during preeclampsia. AT1‐AA (angiotensin 1 receptor auto antibody), TNF‐α (tumor necrosis factor‐α), HIF‐1α (hypoxia inducible factor‐1α), ROS (reactive oxygen species), VEGF (vascular endothelial growth factor), sFlt‐1 (soluble fms‐like tyrosine kinase‐1), PlGF (placental growth factor), sEng (soluble endoglin), ET‐1 (endothelin‐1), NO (nitric oxide).



Figure 1.

Failure of changes in total peripheral vascular resistance (TPR) to cause chronic changes in arterial pressure in several clinical conditions in which the kidneys are functioning normally. In each case, there is a reciprocal relationship between TPR and cardiac output, but no long‐term effect on arterial pressure .



Figure 2.

Time dependency of blood pressure control mechanisms. Approximate maximum feedback gains of various blood pressure control mechanisms at different time intervals after the onset of a disturbance to arterial pressure .



Figure 3.

Block diagram showing the basic elements of the renal‐body fluid feedback mechanism for long‐term regulation of arterial pressure.



Figure 4.

Long‐term effects of increased total peripheral resistance (TPR), such as that caused by closure of a large arteriovenous fistula, with no changes in the renal pressure natriuresis relationship. Blood pressure is initially increased from point A to point B, but elevated blood pressure cannot be sustained because sodium excretion exceeds intake, reducing extracellular fluid volume until blood pressure returns to normal and sodium balance is reestablished .



Figure 5.

Long‐term effects of norepinephrine, a vasoconstrictor that has a relatively weak effect to impair pressure natriuresis. The normal curve (blue) is compared with the vasoconstrictor curve (red line). Initially the vasoconstrictor raises blood pressure (from point A to point B) above the renal set point for sodium balance. However, increased arterial pressure causes a transient natriuresis and decreases extracellular fluid volume until blood pressure eventually stabilizes at a level (point C) at which sodium intake and output are balanced at a reduced extracellular fluid volume .



Figure 6.

Steady‐state relationships between arterial pressure and urinary sodium excretion and sodium intake for subjects with normal kidneys and four general types of renal dysfunction that cause hypertension: decreased kidney mass, increased reabsorption in distal and collecting tubules, reductions in glomerular capillary filtration coefficient (Kf), and increased preglomerular resistance. Note that increased preglomerular resistance causes salt‐insensitive hypertension, whereas the other renal abnormalities cause salt‐sensitive hypertension.



Figure 7.

The effect of reducing kidney mass on salt sensitivity of blood pressure in dogs. Note that as long as sodium chloride intake was normal, surgical reduction of kidney mass by 25% or even 70% did not markedly alter arterial pressure. However, after loss of kidney mass, blood pressure became exquisitely sensitive to high sodium chloride intake .



Figure 8.

Changes in mean arterial pressure during chronic changes in sodium intake in normal control dogs, after angiotensin‐converting enzyme (ACE) inhibition, or after ANG II infusion (5 ng/kg/min) to prevent ANG II from being suppressed when sodium intake was raised .



Figure 9.

Blood pressure (BP) lowering effect of radiofrequency ablation of the renal sympathetic nerves for 18 months (M) in patients who were resistant to the usual antihypertensive drugs. SBP, systolic blood pressure; DBP, diastolic blood pressure .



Figure 10.

Effects of prolonged baroreflex activation by electrical stimulation of carotid sinus nerves on mean arterial pressure and urinary sodium excretion in normal control dogs in dogs that were made hypertensive by infusion of angiotensin II (Ang II) or by feeding a high‐fat diet to produce obesity (Obese). Values for mitogen‐activated protein (MAP) before baroreflex activation: control = 93 ± 1 mm Hg, Ang II hypertension = 129 ± 3 mm Hg, and obese hypertension = 110 ± 3 mm Hg .



Figure 11.

Steady‐state relationships between arterial pressure and sodium intake and excretion under normal conditions with a fully functional RAAS, after blockade of ANG II formation with an angiotensin‐converting enzyme (ACE) inhibitor, and after ANG II infusion at a low dose to prevent ANG II levels from being suppressed when sodium intake was increased. The numbers in parentheses are estimated ANG II levels expressed as times normal .



Figure 12.

Angiotensin (ANG) II increases proximal tubular reabsorption by binding to receptors on the luminal and basolateral membranes and stimulating Na+/H+ antiporter, Na+/HCO3 cotransport, and Na+/K+ adenosine triphosphatase (ATPase) activity. ANG II also increases reabsorption by increasing interstitial fluid colloid osmotic pressure and decreasing interstitial fluid hydrostatic pressure .



Figure 13.

Summary of the pro‐ and antihypertensive actions of endothelin‐1 (ET‐1). The ability of ET‐1 to influence blood pressure and renal pressure natriuresis is highly dependent on where ET‐1 is produced and which renal ET receptor type is activated. ET‐1 can elicit a prohypertensive antinatriuretic effect by activating ETA receptors in the kidneys. Activation of renal ETA receptors increases renal vascular resistance (RVR), which decreases renal plasma flow (RPF) and glomerular filtration rate (GFR), and enhances sodium reabsorption by decreasing peritubular capillary hydrostatic pressure (Pc). The net effect of renal ETA receptor activation is decreased sodium excretion and increased blood pressure. Conversely, ET‐1 can elicit an antihypertensive natriuretic effect via ETB receptor activation. Activation of the renal ETB receptor leads to enhanced synthesis of nitric oxide (NO) and 20‐HETE and suppression of the renin‐angiotensin system. The net effect of renal ETB receptor activation is increased sodium excretion and decreased blood pressure.



Figure 14.

Differences in systolic blood pressure (BP) between collecting duct (CD) endothelin type A and B receptor (ETA/B) KO and control mice on a normal‐ or high‐Na diet .



Figure 15.

Renal mechanisms whereby reduced nitric oxide (NO) synthesis decreases pressure natriuresis and increases blood pressure. Decreased endothelial‐derived nitric oxide (EDNO) synthesis impairs renal sodium excretory function by increasing basal renal vascular resistance, enhancing the renal vascular responsiveness to vasoconstrictors such as ANG II or norepinephrine, or activating the reninangiotensin system. Reductions in NO synthesis also impair sodium excretory function either by directly increasing tubular reabsorption or by altering intrarenal physical factors, such as renal interstitial hydrostatic pressure or medullary blood flow.



Figure 16.

Renal mechanisms whereby reactive oxygen species impair pressure natriuresis and increase blood pressure. An increase in renal oxidative stress impairs renal pressure natriuresis by increasing renal vascular resistance or enhancing tubuloglomerular feedback, both of which decrease the glomerular filtration rate. Renal oxidative stress also reduces sodium excretion by direct effects to increase renal tubular reabsorption.



Figure 17.

Potential mechanisms whereby inhibitors of vascular endothelial growth factor (VEGF) receptor signaling raise blood pressure. Blockade of VEGF receptors results in endothelial dysfunction leading to decreased production of endothelium derived relaxing such as nitric oxide and prostaglandin or enhanced production of vasoconstrictor factors such as thromboxane and endothelin. Inhibitors of VEGF signaling may also result in alterations in glomerular structure and function. These changes may elevate blood pressure by reducing renal blood flow and GFR and impairing the kidney's ability to excrete sodium and water (depicted by a decrease in the pressure natriuresis relationship).



Figure 18.

Proposed role of T cells and inflammation in progression of chronic hypertension. Initial hypertensive stimuli leads to renal injury, neoantigen formation, and eventual T cell activation within the kidney. T‐cell‐derived signals promote entry of other inflammatory cells such as macrophages which result in renal vasoconstriction and sodium reabsorption, thereby increasing the severity of hypertension .



Figure 19.

Summary of the pro‐ and antihypertensive actions of 20‐HETE. 20‐HETE produced in the renal tubules inhibits sodium transport and lowers blood pressure. In the renal vasculature and glomerulus, 20‐HETE is a constrictor that lowers glomerular filtration rate, promotes sodium retention, and increases arterial pressure. In the peripheral circulation, 20‐HETE increases vascular tone and increases blood pressure. TGF, tubuloglomerular feedback; TPR, total peripheral resistance.



Figure 20.

Effect of atrial natriuretic peptide (ANP) receptor knockout on the chronic pressure natriuresis relationship .



Figure 21.

Effect of weight gain to shift the frequency distribution of blood pressure to higher levels. Not all obese subjects have blood pressures in the hypertensive range (> 140/90 mmHg), but excess weight gain raises blood pressure above the baseline level for an individual.



Figure 22.

Summary of mechanisms by which obesity causes hypertension and renal injury. Visceral obesity increases blood pressure by activation of the sympathetic nervous system (SNS), the renin‐angiotensin‐aldosterone system (RAAS), and by physical compression of the kidneys from the fat surrounding the kidneys. SNS activation may be caused by, in part, the effects of leptin, which acts on proopiomelanocortin (POMC) neurons in the hypothalamus and brainstem. Obesity‐induced hypertension and glomerular hyperfiltration may cause renal injury, especially when combined with dyslipidemia and hyperglycemia. Renal injury then exacerbates the hypertension and makes it more difficult to control.



Figure 23.

Possible links among leptin and its effects on the hypothalamus, sympathetic activation, and hypertension. Within the hypothalamus, one of the key pathways of leptin's action on appetite, SNS activity, and blood pressure is stimulation of the proopiomelanocortin (POMC) neurons in the arcuate nucleus (ARC). These neurons send projections to the paraventricular nucleus (PVN) and lateral hypothalamus, releasing α‐melanocyte‐stimulating hormone (α‐MSH), which then acts as an agonist for melanocortin 4 receptors (MC4R). These neurons, in turn, send projections to the nucleus of the solitary tract (NTS) to effect changes in appetite, SNS activity, and blood pressure. Leptin also suppresses the NPY/AGRP neurons, but their role in controlling SNS activity and blood pressure are still unclear. Leptin‐melanocortin activation in distinct areas of the brain and through multiple intracellular signaling pathways may differentially regulate appetite, energy expenditure, and arterial pressure. LH, lateral hypothalamus; RSNA, renal sympathetic nerve activity.



Figure 24.

Changes (Δ) in mean arterial pressure (mmHg), cumulative sodium balance (mmol), and glomerular filtration rate (mL/min) in control, untreated dogs and mineralocorticoid receptor antagonist (eplerenone) treated (10 mg/kg, twice daily) dogs that were fed a high fat diet for 5 weeks to develop obesity .



Figure 25.

Adjusted relative risk for end stage renal disease by body mass index (BMI) in 320,252 subjects. Model adjusted for Multiphasic Health Checkup period, age, sex, race, education level, smoking status, history of myocardial infarction, serum cholesterol level, proteinuria, hematuria, and serum creatinine level. Error bars represent 95% confidence intervals .



Figure 26.

Cardiovascular, metabolic, and renal disease associated with visceral obesity which appears to be a primary cause of all of cluster of CVD risk factors in the metabolic syndrome. CRP, C‐reactive protein; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; PAI, platelet activator inhibitor; PP, postprandial; RAAS, renin‐angiotensin‐aldosterone system; SNS, sympathetic nervous system; TG, triglycerides.



Figure 27.

Effect of placing a constricting clamp on the renal artery of one kidney after removal of the contralateral kidney (one‐kidney, 1‐clip Goldblatt hypertension) .



Figure 28.

Effects of chronic aldosterone infusion when renal perfusion pressure was servo controlled (red lines) or allowed to increase (blue lines). When renal perfusion pressure was prevented from increasing, “escape” from sodium retention did not occur and cumulative sodium balance and systemic arterial pressure continued to increase .



Figure 29.

Mechanisms linking placental ischemia and hypertension during preeclampsia. AT1‐AA (angiotensin 1 receptor auto antibody), TNF‐α (tumor necrosis factor‐α), HIF‐1α (hypoxia inducible factor‐1α), ROS (reactive oxygen species), VEGF (vascular endothelial growth factor), sFlt‐1 (soluble fms‐like tyrosine kinase‐1), PlGF (placental growth factor), sEng (soluble endoglin), ET‐1 (endothelin‐1), NO (nitric oxide).

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John E. Hall, Joey P. Granger, Jussara M. do Carmo, Alexandre A. da Silva, John Dubinion, Eric George, Shereen Hamza, Joshua Speed, Michael E. Hall. Hypertension: Physiology and Pathophysiology. Compr Physiol 2012, 2: 2393-2442. doi: 10.1002/cphy.c110058