Pulmonary hypertension (PH) is characterized by an increase in pulmonary vascular resistance that impedes the ejection of blood by the right ventricle, ultimately leading to right ventricular failure. The most common cause of PH is alveolar hypoxia-related, for instance, to high altitude or chronic hypoxemic lung disease. Acute exposure of various mammals to hypoxia results within a few minutes in pulmonary vasoconstriction related to contraction of the smooth muscle cells (SMCs) in the distal pulmonary arteries. With chronic exposure, PH is due not only to SMC contraction and polycythemia but also to structural remodeling of the pulmonary arteries (25). Thus, preexisting SMCs in normally muscularized pulmonary arteries undergo hypertrophy and hyperplasia, while new SMCs appear in intraacinar arteries that are normally nonmuscularized or muscularized only along part of their circumference. Another component of hypoxia-induced pulmonary artery remodeling is extracellular matrix deposition in the vessel wall, with a build-up of connective tissue proteins such as elastin and collagen,. Reversibility is a remarkable feature of chronic hypoxic PH. Although correcting alveolar hypoxia may have little or no effect on PH in the short term, PH caused by chronic hypoxia resolves over several weeks or months after the return to normoxia.
The classic understanding of chronic hypoxic PH is based on the concept that vascular remodeling is a consequence of sustained pulmonary vasoconstriction and increased pulmonary artery pressure. The resulting increase in shear stress is thought to trigger hypertrophy and proliferation of the vascular SMCs (Fig. 1). Although this concept remains valid in many aspects, it is no longer viewed as the only pathophysiological mechanism of hypoxic PH. Recent evidence shows that hypoxia-induced pulmonary vascular remodeling can be attenuated despite enhanced hypoxic pulmonary vasoconstriction. This suggests that some of the vasoconstricting substances released in hypoxic lung tissue, most notably endothelin (ET) and serotonin (5-hydroxytryptamine), may serve as growth factors for vascular SMCs, or exert other functions independent from their effects on vascular tone and from the severity of pulmonary vasoconstriction. Another recently identified mechanism that may be involved in hypoxia-induced pulmonary vascular remodeling is a direct effect of hypoxia on the expression of specific genes acting on SMCs, endothelial cells, fibroblasts, or extracellular matrix remodeling (Fig. 1).
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