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Pulmonary hypertension (PH) is a common complication of chronic hypoxic lung diseases, which increase morbidity and mortality. Hypoxic PH has previously been attributed to structural changes in the pulmonary vasculature including narrowing of the vascular lumen and loss of vessels, which produce a fixed increase in resistance. Using quantitative stereology, we now show that chronic hypoxia caused PH and remodeling of the blood vessel walls in rats but that this remodeling did not lead to structural narrowing of the vascular lumen. Sustained inhibition of the RhoA/Rho-kinase pathway throughout the period of hypoxic exposure attenuated PH and prevented remodeling in intra-acinar vessels without enlarging the structurally determined lumen diameter. In chronically hypoxic lungs, acute Rho kinase inhibition markedly decreased PVR but did not alter the alveolar to arterial oxygen gap. In addition to increased vascular resistance, chronic hypoxia induced Rho kinase-dependent capillary angiogenesis. Thus, hypoxic PH was not caused by fixed structural changes in the vasculature but by sustained vasoconstriction, which was largely Rho kinase dependent. Importantly, this vasoconstriction had no role in ventilation-perfusion matching and optimization of gas exchange. Rho kinase also mediated hypoxia-induced capillary angiogenesis, a previously unrecognized but potentially important adaptive response.

Original publication

DOI

10.1161/01.res.0000174287.17953.83

Type

Journal

Circulation research

Publication Date

07/2005

Volume

97

Pages

185 - 191

Addresses

Department of Physiology, University College, Earlsfort Terrace, Dublin 2, Ireland.

Keywords

Lung, Capillaries, Animals, Rats, Hypertension, Pulmonary, Amides, Pyridines, rhoA GTP-Binding Protein, Vascular Endothelial Growth Factor A, Intracellular Signaling Peptides and Proteins, Enzyme Inhibitors, Oxygen Consumption, Blood Pressure, Vascular Resistance, Vasoconstriction, Neovascularization, Physiologic, Male, rho-Associated Kinases, Hypoxia, Protein Serine-Threonine Kinases