Vascular Remodeling Versus Vasoconstriction in Chronic Hypoxic Pulmonary Hypertension

Abstract

C hronic or sustained pulmonary hypertension is a complication of residence at high altitudes and chronic lung diseases such as chronic obstructive pulmonary disease, cystic fibrosis, bronchiectasis, asthma, and sleep apnea. Alveolar hypoxia is an important (though probably not exclusive) contributor to the pulmonary hypertension observed in these conditions. Further, it is widely accepted that secondary hypoxic pulmonary hypertension is strongly associated with increased morbidity and reduced survival. 1,2 These facts have led to intense research efforts to identify the underlying mechanisms contributing to this condition, with the ultimate goal of identifying and developing novel therapeutic interventions. This work has relied heavily on the use of animal models, and one of the most commonly used is exposure of rats to chronic-hypoxic conditions by nitrogen dilution or hypobaria. Observations, predominately in this model, have led to the longstanding and widely accepted theory that chronic hypoxic pulmonary hypertension results from a combination of sustained vasoconstriction and vascular remodeling. It is generally believed that the contribution of vasoconstriction is greatest early in the disease process and that structural remodeling of the pulmonary vascular bed becomes progressively more important over time. That structural change is an important determinant of increased resistance and pressure in chronic pulmonary hypertension is supported by observations that over time of exposure to hypoxia, acute reexposure to normal or even high levels of inspired oxygen becomes progressively less effective in reducing the pulmonary arterial pressure. This lack of responsiveness to oxygen, or even to other pulmonary vasodilators such as Ca 2ϩ channel blockers, has led to the concept that chronic hypoxic pulmonary hypertension is associated with a "fixed" structural component responsible for the increased pulmonary vascular resistance. The structural changes thought to contribute to the increased vascular resistance have been broadly characterized into 2 processes: (1) inward remodeling of the pulmonary artery wall and (2) a reduction in the total number of small peripheral pulmonary arteries (a process referred to as rarefaction or pruning of the pulmonary vasculature).The work presented by Hyvel et al challenges, at least in certain ways, both of these concepts. 3 Pulmonary vascular remodeling refers to a process that causes thickening of the arterial wall and is thought to increase resistance by physical encroachment of the lumen of small peripheral pulmonary arteries and arterioles. Because intimal thickening is not usually observed in hypoxic pulmonary hypertension, this reduction in luminal area is believed to be attributable largely to constrictive medial and adventitial thickening. However, using different lung preparation techniques than have been used in most other hypoxic studies (ie, the pulmonary vasculature was "maximally" vasodilated by perfusion with calcium-free plus EGTA physiological saline solution...

Contribution of xanthine oxidase-derived superoxide to chronic hypoxic pulmonary hypertension in neonatal rats

“…Inset (top right): complete lack of staining in a section from a hypoxia-exposed, vehicle-treated animal where the primary antibody was preadsorbed with 100 mM 3-nitrotyrosine. ally, changes seen in remodeled pulmonary resistance arteries were largely characterized by medial wall thickening without evidence of severe luminal encroachment, suggesting that chronic PHT in this model is likely to be caused by enhanced and sustained vasoconstriction (contributed to by thickening of the medial smooth muscle layer and endothelial dysfunction) rather than by luminal obstruction (58). This likelihood is supported by our recent findings demonstrating that increased pulmonary vascular resistance that does not respond to "conventional" vasodilators (suggesting a fixed pathological process) can be acutely normalized by inhibition of Rho-kinase, a signaling peptide that modulates Ca 2ϩ sensitivity in smooth muscle (51).…”

MicroRNA-206 is involved in hypoxia-induced pulmonary hypertension through targeting of the HIF-1α/Fhl-1 pathway

“…34 In the process of PH, vascular remodeling contributes to a sustained elevation of pulmonary vascular resistance and pulmonary artery pressure as a result of vascular remodeling characterized largely by vascular smooth muscle cell proliferation and medial hypertrophy. 35,36 Table 5 The muscle-specific miRNA-1 family…”

Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability

“…35,36 Whether plexiform vascular lesions develop in humans only in the advanced stages of pulmonary hypertension is controversial, 78,79 and pulmonary hypertension is not always associated with vascular remodeling. 80 Current understanding of the pathogenesis of early human pulmonary arterial hypertension is that pulmonary arteries and arterioles have abnormally high vasoconstrictor tone, and the initial vascular defect is functional rather than structural, just as the cardiac catheterization studies demonstrate in these sickle mice.…”