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Hypoxic Pulmonary Hypertension of the Newborn

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Abstract

Hypoxic pulmonary hypertension of the newborn is characterized by elevated pulmonary vascular resistance and pressure due to vascular remodeling and increased vessel tension secondary to chronic hypoxia during the fetal and newborn period. In comparison to the adult, the pulmonary vasculature of the fetus and the newborn undergoes tremendous developmental changes that increase susceptibility to a hypoxic insult. Substantial evidence indicates that chronic hypoxia alters the production and responsiveness of various vasoactive agents such as endothelium‐derived nitric oxide, endothelin‐1, prostanoids, platelet‐activating factor, and reactive oxygen species, resulting in sustained vasoconstriction and vascular remodeling. These changes occur in most cell types within the vascular wall, particularly endothelial and smooth muscle cells. At the cellular level, suppressed nitric oxide‐cGMP signaling and augmented RhoA‐Rho kinase signaling appear to be critical to the development of hypoxic pulmonary hypertension of the newborn. © 2011 American Physiological Society. Compr Physiol 1:61‐79, 2011.

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Figure 1. Figure 1.

Diagram showing postnatal structural changes and the effect of chronic hypoxia in pulmonary arteries based on studies with fetal and newborn piglets . Fetal pulmonary arteries have thick walls and narrow lumen. Smooth muscle cells (SMCs) are rounded, densely packed, and appear immature and synthetic in type and contractile organelles do not predominate. After birth, the overlap of adjacent SMCs rapidly decreases and a reorganization of the cytoskeleton occurs within 1 week of life so that the SMCs become thinner and spread around a larger lumen. Later, the medial thickness of the vessel wall decreases further to mature levels at about 6‐month old with reduced cell packing density and increased myofilament density. The shape of SMCs is elongated with stable cytoskeleton. Postnatal exposure to chronic hypoxia prevents these postnatal adaptive changes and promotes SMC proliferation and/or hypertrophy, leading to thickened vessel wall and narrowed vessel lumen. The shape of SMCs is more rounded because of abnormal cytoskeletal composition and organization.

Figure 2. Figure 2.

Possible mechanisms for vascular remodeling caused by ET‐1 in perinatal lungs. ET‐1 may promote smooth muscle cell (SMC) proliferation by activating transforming growth factor β (TGF‐β)‐Smad signaling and by inhibiting apoptosis through phosphoinositide 3‐kinase (PI3K)/AKT and p38 mitogen‐activated protein kinase pathway . ET‐1 may also increase the extracellular matrix deposition through increasing the release of TGF‐β and by inhibiting the activity of metalloproteinases (MMPs) and stimulating the activity of the tissue inhibitors of metalloproteinases (TIMPs) . The dashed line indicates inhibitory action.

Figure 3. Figure 3.

A possible mechanism for perinatal pulmonary vascular smooth muscle cells (SMCs) to switch from contractile to proliferation phenotype induced by hypoxia‐induced downregulation of PKG. Myocardin, a transcriptional coactivator of serum response factor (SRF), is upregulated by PKG under normoxia. Consequently, more myocardin is associated with SRF, which leads to SMC marker gene expression and the cells at contractile phenotype. Under hypoxia, the depressed PKG level results in decreased myocardin expression and consequently increased binding of E‐26‐like protein 1(Elk‐1) to SRF. The binding of phosphorylated Elk‐1 to SRF leads to suppression of SMC marker genes and activation of expression of genes involved in cell proliferation (modified from reference , with permission).

Figure 4. Figure 4.

Effects of hypoxia on perinatal pulmonary vasodilatation caused by endothelial nitric oxide (NO). Hypoxia reduces the release of endothelial NO by directly inhibiting eNOS activity, as oxygen is necessary for the conversion of l‐arginine to NO and l‐citrulline and by downregulating eNOS mRNA and protein expression. Hypoxia may impair the l‐arginine uptake and inhibit eNOS through the downregulation of dimethyl‐arginine dimethylaminohydrolase (DDAH), an enzyme that degrades asymmetric dimethylarginine (ADMA), an endogenous inhibitor of eNOS . NO causes vasodilatation primarily via elevating cGMP level through soluble guanylyl cyclase (sGC) followed by stimulating cGMP‐dependent protein kinase (PKG). Hypoxia may downregulate the expressions and activities of sGC and PKG . Hypoxia may also augment the degradation of cGMP by increasing the activity of phosphodiesterase type 5 (PDE5) . The dashed line indicates inhibitory action.

Figure 5. Figure 5.

Possible signal transduction pathways in pulmonary arteries for the opposing actions of PKG and RhoA‐ROCK and the effects of chronic hypoxia. Chronic hypoxia may increase the Ca2+ sensitivity of the contractile filaments of smooth muscle through the inhibition of myosin light‐chain phosphatase (MLCP) via RhoA‐ROCK pathway. ROCKs inhibit MLCP by phosphorylating the regulatory subunit of MLCP (MYPT1) at Thr696 and Thr853 (human sequence). ROCK may also inhibit the activity of MLCP through phosphorylation of PKC‐potentiated inhibitor protein of 17 kDa (CPI‐17). Activation of PKG by nitric oxide (NO) and cGMP may interfere with the activation of RhoA. PKG may phosphorylate MYPT1 at Ser695 and Ser852, which results in a decreased ROCK‐mediated phosphorylation of MYPT1 at Thr696 and Thr853. This antagonizing effect of PKG may be impaired by chronic hypoxia. PKG can also directly stimulate MLCP activity through interaction between the leucine zipper (LZ) motives of PKG and MYPT1. GPCR, G‐protein‐coupled receptors; G, G protein; DAG, diacylglycerol; RhoA, a small monomeric GTPase; M20, a 20‐kDa subunit of MLCP with unknown function. The dashed line indicates inhibitory action (modified from reference , with permission).



Figure 1.

Diagram showing postnatal structural changes and the effect of chronic hypoxia in pulmonary arteries based on studies with fetal and newborn piglets . Fetal pulmonary arteries have thick walls and narrow lumen. Smooth muscle cells (SMCs) are rounded, densely packed, and appear immature and synthetic in type and contractile organelles do not predominate. After birth, the overlap of adjacent SMCs rapidly decreases and a reorganization of the cytoskeleton occurs within 1 week of life so that the SMCs become thinner and spread around a larger lumen. Later, the medial thickness of the vessel wall decreases further to mature levels at about 6‐month old with reduced cell packing density and increased myofilament density. The shape of SMCs is elongated with stable cytoskeleton. Postnatal exposure to chronic hypoxia prevents these postnatal adaptive changes and promotes SMC proliferation and/or hypertrophy, leading to thickened vessel wall and narrowed vessel lumen. The shape of SMCs is more rounded because of abnormal cytoskeletal composition and organization.



Figure 2.

Possible mechanisms for vascular remodeling caused by ET‐1 in perinatal lungs. ET‐1 may promote smooth muscle cell (SMC) proliferation by activating transforming growth factor β (TGF‐β)‐Smad signaling and by inhibiting apoptosis through phosphoinositide 3‐kinase (PI3K)/AKT and p38 mitogen‐activated protein kinase pathway . ET‐1 may also increase the extracellular matrix deposition through increasing the release of TGF‐β and by inhibiting the activity of metalloproteinases (MMPs) and stimulating the activity of the tissue inhibitors of metalloproteinases (TIMPs) . The dashed line indicates inhibitory action.



Figure 3.

A possible mechanism for perinatal pulmonary vascular smooth muscle cells (SMCs) to switch from contractile to proliferation phenotype induced by hypoxia‐induced downregulation of PKG. Myocardin, a transcriptional coactivator of serum response factor (SRF), is upregulated by PKG under normoxia. Consequently, more myocardin is associated with SRF, which leads to SMC marker gene expression and the cells at contractile phenotype. Under hypoxia, the depressed PKG level results in decreased myocardin expression and consequently increased binding of E‐26‐like protein 1(Elk‐1) to SRF. The binding of phosphorylated Elk‐1 to SRF leads to suppression of SMC marker genes and activation of expression of genes involved in cell proliferation (modified from reference , with permission).



Figure 4.

Effects of hypoxia on perinatal pulmonary vasodilatation caused by endothelial nitric oxide (NO). Hypoxia reduces the release of endothelial NO by directly inhibiting eNOS activity, as oxygen is necessary for the conversion of l‐arginine to NO and l‐citrulline and by downregulating eNOS mRNA and protein expression. Hypoxia may impair the l‐arginine uptake and inhibit eNOS through the downregulation of dimethyl‐arginine dimethylaminohydrolase (DDAH), an enzyme that degrades asymmetric dimethylarginine (ADMA), an endogenous inhibitor of eNOS . NO causes vasodilatation primarily via elevating cGMP level through soluble guanylyl cyclase (sGC) followed by stimulating cGMP‐dependent protein kinase (PKG). Hypoxia may downregulate the expressions and activities of sGC and PKG . Hypoxia may also augment the degradation of cGMP by increasing the activity of phosphodiesterase type 5 (PDE5) . The dashed line indicates inhibitory action.



Figure 5.

Possible signal transduction pathways in pulmonary arteries for the opposing actions of PKG and RhoA‐ROCK and the effects of chronic hypoxia. Chronic hypoxia may increase the Ca2+ sensitivity of the contractile filaments of smooth muscle through the inhibition of myosin light‐chain phosphatase (MLCP) via RhoA‐ROCK pathway. ROCKs inhibit MLCP by phosphorylating the regulatory subunit of MLCP (MYPT1) at Thr696 and Thr853 (human sequence). ROCK may also inhibit the activity of MLCP through phosphorylation of PKC‐potentiated inhibitor protein of 17 kDa (CPI‐17). Activation of PKG by nitric oxide (NO) and cGMP may interfere with the activation of RhoA. PKG may phosphorylate MYPT1 at Ser695 and Ser852, which results in a decreased ROCK‐mediated phosphorylation of MYPT1 at Thr696 and Thr853. This antagonizing effect of PKG may be impaired by chronic hypoxia. PKG can also directly stimulate MLCP activity through interaction between the leucine zipper (LZ) motives of PKG and MYPT1. GPCR, G‐protein‐coupled receptors; G, G protein; DAG, diacylglycerol; RhoA, a small monomeric GTPase; M20, a 20‐kDa subunit of MLCP with unknown function. The dashed line indicates inhibitory action (modified from reference , with permission).

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Yuansheng Gao, J Usha Raj. Hypoxic Pulmonary Hypertension of the Newborn. Compr Physiol 2010, 1: 61-79. doi: 10.1002/cphy.c090015