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Hypoxic pulmonary hypertension (HPH) contributes to the morbidity and mortality of adult and pediatric patients with various lung and heart diseases. The pathogenesis of HPH comprises sustained vasoconstriction, and structural remodeling of the pulmonary arteries that is characterized by medial and adventitial thickening of muscular arteries and muscularization of the normally non-muscular arterioles (28). The vasoconstriction involves direct hypoxic activation of vascular smooth muscle and endothelial cells, increased activity of vasoconstrictors such as endothelin-1 (ET-1) and serotonin (5-HT), and deficient activity of vasodilators such as nitric oxide (NO) and prostacyclin (PGI2). The hypoxic activation and mediator imbalance are also implicated in the complex pathobiology of pulmonary arterial wall thickening that includes medial smooth muscle and adventitial fibroblast cell growth and migration, and deposition of extracellular matrix proteins.

The role of intracellular signaling via the small GTPase RhoA and its downstream effector Rho-associated kinase (Rho/Rho-kinase signaling) in the pathogenesis of HPH is unknown. However, recent advances in the cell biology and pathophysiology of this signal transduction pathway in the systemic circulation suggest that it may play important roles in both the sustained vasoconstriction and arterial remodeling of HPH. The importance of Rho/Rho-kinase-mediated Ca2+ sensitization of vascular smooth muscle cell (VSMC) contraction in acute hypoxic pulmonary vasoconstriction (HPV) is reviewed in Chapter 7 of this book. The objective here is to provide an overview of Rho/Rho-kinase signaling and to detail the emerging evidence that it is also involved in the pulmonary vascular response to chronic hypoxia (Fig. 1).

Chronic Hypoxia

t Rho-kinase t ET-1 & 5-HT — GTP-RhoA — | NO & PGI2

t Rho-kinase

Ca1+ Sensitization

Cell Growth & Migration

Sustained Vasoconstriction

Vascular Remodeling

Figure I. Overview of the postulated role of Rho/Rho-kinase signaling in the pathogenesis of HPH. Chronic hypoxia and/or the associated increased activity of vasoconstrictors such as ET-1 and 5-HT, and decreased activity of vasodilators such as NO and PGI2, activate RhoA which then stimulates Rho-kinase. Rho-kinase contributes to pulmonary hypertension by: mediating Ca2+ sensitization of arterial smooth muscle cell contraction and sustained pulmonary vasoconstriction, promoting vascular smooth muscle and fibroblast cell growth and migration and vascular remodeling, and regulating the expression of genes involved in increased activity of vasoconstrictors and deficient production of vasodilators.

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Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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