Faculty Collaboration Database

Rho kinase and Na⁺ /H⁺ exchanger mediate endothelin-1-induced pulmonary arterial smooth muscle cell proliferation and migration. Physiol Rep 2018 May;6(9):e13698

Date

05/15/2018

Pubmed ID

29756391

Pubmed Central ID

PMC5949284

DOI

10.14814/phy2.13698

Scopus ID

2-s2.0-85046996880 (requires institutional sign-in at Scopus site)   15 Citations

Abstract

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 PASMCs via a mechanism requiring Rho kinase (ROCK). However, whether ROCK and/or increased NHE activity mediate ET-1-induced migration and proliferation in PASMCs remains unknown. In this study, we used fluorescent microscopy in transiently cultured PASMCs 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 NHE1 expression, but increased pH_i , NHE activity, migration, and proliferation in rat PASMCs. 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.

Author List

Huetsch JC, Walker J, Undem C, Lade J, Yun X, Baksh S, Jiang H, Lai N, Shimoda LA

Author

Jasmine Walker MD, MPH Assistant Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cell Movement
Cell Proliferation
Endothelin-1
Hydrogen-Ion Concentration
Male
Muscle, Smooth, Vascular
Primary Cell Culture
Pulmonary Artery
Rats, Wistar
Sodium-Hydrogen Exchangers
rho-Associated Kinases