Document Detail


Rho kinase modulates postnatal adaptation of the pulmonary circulation through separate effects on pulmonary artery endothelial and smooth muscle cells.
MedLine Citation:
PMID:  20709731     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
At birth, pulmonary vasodilation occurs concomitant with the onset of air-breathing life. Whether and how Rho kinase (ROCK) modulates the perinatal pulmonary vascular tone remains incompletely understood. To more fully characterize the separate and interactive effects of ROCK signaling, we hypothesized that ROCK has discrete effects on both pulmonary artery (PA): 1) endothelial cell (PAEC) nitric oxide (NO) production and contractile state; and 2) smooth muscle cell tone independent of endothelial NO synthase (eNOS) activity. To test these hypotheses, NO production and endothelial barrier function were determined in fetal PAEC under baseline hypoxia and following exposure to normoxia with and without treatment with Y-27632, a specific pharmacological inhibitor of ROCK. In acutely instrumented, late-gestation ovine fetuses, eNOS was inhibited by nitro-l-arginine infusion into the left PA (LPA). Subsequently, fetal lambs were mechanically ventilated (MV) with 100% oxygen in the absence (control period) and presence of Y-27632. In PAEC, treatment with Y-27632 had no effect on cytosolic calcium but did increase normoxia-induced NO production. Moreover, acute normoxia increased PAEC barrier function, an effect that was potentiated by Y-27632. In fetal lambs, MV during the control period had no effect on LPA flow. In contrast, MV after Y-27632 increased LPA flow and fetal arterial P(O)₂ (Pa(O₂)) and decreased PA pressure. In conclusion, ROCK activity modulates vascular tone in the perinatal pulmonary circulation via combined effects on PAEC NO production, barrier function, and smooth muscle tone. ROCK inhibition may represent a novel treatment strategy for neonatal pulmonary vascular disease.
Authors:
Cristina M Alvira; David J Sukovich; Shu-Chen Lyu; David N Cornfield
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-08-13
Journal Detail:
Title:  American journal of physiology. Lung cellular and molecular physiology     Volume:  299     ISSN:  1522-1504     ISO Abbreviation:  Am. J. Physiol. Lung Cell Mol. Physiol.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-12-06     Completed Date:  2011-01-13     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  100901229     Medline TA:  Am J Physiol Lung Cell Mol Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  L872-8     Citation Subset:  IM    
Affiliation:
Center for Excellence in Pulmonary Biology, Dept. of Pediatrics, Stanford Univ. Medical School, CA 94305, USA.
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MeSH Terms
Descriptor/Qualifier:
Adaptation, Physiological*
Animals
Calcium / metabolism
Cells, Cultured
Endothelial Cells / cytology,  physiology*
Female
Fetus / anatomy & histology,  physiology
Myocytes, Smooth Muscle / cytology,  physiology*
Nitric Oxide / metabolism
Pregnancy
Pulmonary Artery / cytology*
Pulmonary Circulation / physiology*
Sheep
rho-Associated Kinases / metabolism*
Grant Support
ID/Acronym/Agency:
R01-HL-60784/HL/NHLBI NIH HHS; R01-HL-70628/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
10102-43-9/Nitric Oxide; 7440-70-2/Calcium; EC 2.7.11.1/rho-Associated Kinases
Comments/Corrections

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