Rho kinase-mediated vasoconstriction in pulmonary hypertension.

Abstract

Rho kinase-mediated vasoconstriction rather than fixed arterial wall thickening is responsible for increased pulmonary vascular resistance and pulmonary hypertension in chronically hypoxic and monocrotaline-injected rats. In the absence of vascular tone, the medial and adventitial thickening in these models has only minimal impact on the cross-sectional area of the pulmonary arterial bed. In contrast, increased pulmonary vascular resistance in left-pneumonectomized plus monocrotaline-injected rats and VEGF receptor blocker-injected plus chronic hypoxia rats is attributable to both Rho kinase-mediated vasoconstriction and formation of lumen obliterating lesions in small pulmonary arteries. The upstream signals responsible for activation of RhoA/Rho kinase signaling in hypertensive pulmonary arteries and whether or not they differ in different forms of pulmonary hypertension are unclear. The RhoA/Rho kinase pathway is a convergence point of several different vasoconstrictor signals, including those mediated by G protein-coupled receptors, receptor tyrosine kinases, and integrin clustering. Both isoforms of Rho kinase can also be constitutively activated by cleavage, and cleaved Rho kinase 1 has been detected in the hypertensive lungs of left-pneumonectomized plus monocrotaline-injected rats. That such diverse stimuli can lead to activation of Rho kinase, which may cause hypercontraction of smooth muscle by promoting both actomyosin interaction and remodeling of the cytoskeleton, may explain why in various rat models of pulmonary hypertension Rho kinase inhibitors are more effective pulmonary vasodilators than conventional agents such as nitric oxide, prostacyclin, and nifedipine. We suspect the same will be true in at least some forms of human pulmonary arterial hypertension.

• Authors: Ivan F McMurtry, Kohtaro Abe, Hiroki Ota, Karen A Fagan, Masahiko Oka
• Journal: Advances in experimental medicine and biology (Adv Exp Med Biol) Vol. 661 Pg. 299-308 ( 2010) ISSN: 0065-2598 [Print] United States
• PMID: 20204738 (Publication Type: Journal Article, Review)

Chemical References

• rho-Associated Kinases
• Bone Morphogenetic Protein Receptors, Type II
• rhoA GTP-Binding Protein

Topics

• Animals
• Bone Morphogenetic Protein Receptors, Type II (genetics, metabolism)
• Humans
• Hypertension, Pulmonary (pathology, physiopathology)
• Lung (blood supply, metabolism, pathology)
• Muscle Contraction (physiology)
• Muscle, Smooth, Vascular (cytology, physiology)
• Myocytes, Smooth Muscle (cytology, physiology)
• Signal Transduction (physiology)
• Vasoconstriction (physiology)
• rho-Associated Kinases (metabolism)
• rhoA GTP-Binding Protein (metabolism)