Roles for Vasoconstriction and Gene Expression in Hypoxia-induced Pulmonary Vascular Remodeling

Summary

The development and maintenance of hypoxia-induced pulmonary vascular remodeling is not related only to the precapillary pressure increase and shear stress that result from pulmonary vasoconstriction. The recent finding that several mammalian species and mice with 5-HTT deficiency show little hypoxic pulmonary vascular remodeling despite a strong acute hypoxic pressor response suggests that precapillary vasoconstriction may not fully explain the pathophysiology of hypoxic PH. SMC proliferation, the main component of hypoxic pulmonary vascular remodeling, may be best viewed as a process linked to the direct effect of hypoxia on the expression of various genes. Exposure to hypoxia has been shown to downregulate K _gn -channel ga subunits in SMCs from pulmonary arteries, thereby decreasing K⁺ flows and increasing cytoplasmic Ca²⁺ concentrations in these cells. The effect of hypoxia on gene expression may also alter the balance between pro-and anti-proliferative factors derived from the endothelium. Hypoxia increases the expression of ET-1 and PDGF and decreases the expression of heparan sulfate, prostacyclin synthase, and eNOS synthase. Hypoxia is also known to increase the transcription rate of various genes involved in vascular remodeling through hypoxia-inducible transcription factors. VEGF, which is the product of one of the genes containing functionally important binding sites for HIF-1, may protect against the development of hypoxic PH by stimulating angiogenic processes. Recent experimental findings demonstrate that an increase in the transcription rate of the 5-HTT gene in response to hypoxia plays a major role in pulmonary SMC proliferation. 5-HTT expression is genetically controlled, and a polymorphism in the promoter region of the human gene affects transcriptional activity, the long promoter variant of the gene being associated with increased expression as compared with the short variant. The ability of SMCs to proliferate in response to 5-HT is linked to this functional polymorphism, which may confer susceptibility to various forms of PH in humans, most notably chronic hypoxic PH.

The recent finding that several factors, including 5-HT and ET, are involved not only in experimental hypoxic PH but also in human primary PH suggests that common mechanisms lead to pulmonary vascular remodeling, whatever the inciting causal factor. This provides a strong rationale for actively investigating the mechanisms that underlie the complex vascular changes responsible for the hypoxia-induced pulmonary vascular remodeling. Such studies may identify new molecular pathways involved in various types of PH.