Inhibition of Rho-kinase attenuates hypoxia-induced angiogenesis in the pulmonary circulation

Jean Marc Hyvelin, Katherine Howell, Alistair Nichol, Christine M. Costello, Robert J. Preston, Paul McLoughlin

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Abstract

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 languageEnglish
Pages (from-to)185-191
Number of pages7
JournalCirculation Research
Volume97
Issue number2
DOIs
Publication statusPublished - 22 Jul 2005

Keywords

  • Angiogenesis
  • Pulmonary hypertension
  • Rho-kinase
  • RhoA
  • Y-27632

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