Open AccessRho kinase and Na + /H + exchanger mediate endothelin‐1‐induced pulmonary arterial smooth muscle cell proliferation and migration
Author(s) -
Huetsch John C.,
Walker Jasmine,
Undem Clark,
Lade Julie,
Yun Xin,
Baksh Syeda,
Jiang Haiyang,
Lai Ning,
Shimoda Larissa A.
Publication year - 2018
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.13698
Subject(s) - intracellular ph , cell growth , endothelin 1 , intracellular , pulmonary hypertension , homeostasis , chemistry , vascular smooth muscle , cell migration , sodium–hydrogen antiporter , rho associated protein kinase , microbiology and biotechnology , medicine , endocrinology , cell , kinase , biology , smooth muscle , biochemistry , receptor , sodium , organic chemistry
Excessive production of endothelin‐1 ( ET ‐1) has been observed in almost all forms of pulmonary hypertension. ET ‐1, a highly potent vasoconstrictor, can also potentiate pulmonary arterial smooth muscle cell ( PASMC ) growth and migration, both of which contribute to the vascular remodeling that occurs during the development of pulmonary hypertension. Increasing evidence indicates that alkalinization of intracellular pH ( pH i ), typically due to activation of Na + /H + exchange ( NHE ), is associated with enhanced PASMC proliferation and migration. We recently demonstrated that application of exogenous ET ‐1 increased NHE activity in murine PASMC s via a mechanism requiring Rho kinase ( ROCK ). However, whether ROCK and/or increased NHE activity mediate ET ‐1‐induced migration and proliferation in PASMC s remains unknown. In this study, we used fluorescent microscopy in transiently cultured PASMC s from distal pulmonary arteries of the rat and the pH ‐sensitive dye, BCECF ‐ AM , to measure changes in resting pH i and NHE activity induced by exposure to exogenous ET ‐1 (10 −8 mol/L) for 24 h. Cell migration and proliferation in response to ET ‐1 were also measured using Transwell assays and BrdU incorporation, respectively. We found that application of exogenous ET ‐1 had no effect on NHE 1 expression, but increased pH i , NHE activity, migration, and proliferation in rat PASMC s. Pharmacologic inhibition of NHE or ROCK prevented the ET ‐1‐induced changes in cell function (proliferation and migration). Our results indicate that ET ‐1 modulates PASMC migration and proliferation via changes in pH i homeostasis through a pathway involving ROCK .