Pulmonary artery smooth muscle cell endothelin-1 expression modulates the pulmonary vascular response to chronic hypoxia.
Endothelin-1 (ET-1) increases pulmonary vascular tone through direct effects on pulmonary artery smooth muscle cells (PASMC) via membrane-bound ET-1 receptors. Circulating ET-1 contributes to vascular remodeling by promoting SMC proliferation and migration and inhibiting SMC apoptosis. Although endothelial cells (EC) are the primary source of ET-1, whether ET-1 produced by SMC modulates pulmonary vascular tone is unknown. Using transgenic mice created by crossbreeding SM22α-Cre mice with ET-1(flox/flox) mice to selectively delete ET-1 in SMC, we tested the hypothesis that PASMC ET-1 gene expression modulates the pulmonary vascular response to hypoxia. ET-1 gene deletion and selective activity of SM22α promoter-driven Cre recombinase were confirmed. Functional assays were performed under normoxic (21% O2) or hypoxic (5% O2) conditions using murine PASMC obtained from ET-1(+/+) and ET-1(-/-) mic and in human PASMC (hPASMC) after silencing of ET-1 using siRNA. Under baseline conditions, there was no difference in right ventricular systolic pressure (RVSP) between SM22α-ET-1(-/-) and SM22α-ET-1(+/+) (control) littermates. After exposure to hypoxia (10% O2, 21-24 days), RVSP was and vascular remodeling were less in SM22α-ET-1(-/-) mice compared with control littermates (P < 0.01). Loss of ET-1 decreased PASMC proliferation and migration and increased apoptosis under normoxic and hypoxic conditions. Exposure to selective ET-1 receptor antagonists had no effect on either the hypoxia-induced hPASMC proliferative or migratory response. SMC-specific ET-1 deletion attenuates hypoxia-induced increases in pulmonary vascular tone and structural remodeling. The observation that loss of ET-1 inhibited SMC proliferation, survival, and migration represents evidence that ET-1 derived from SMC plays a previously undescribed role in modulating the response of the pulmonary circulation to hypoxia. Thus PASMC ET-1 may modulate vascular tone independently of ET-1 produced by EC.
Center for Excellence in Pulmonary Biology, Division of Pulmonary, Asthma and Sleep Medicine, Department of Pediatrics, Stanford University Medical School, Stanford, California.
Francis Y
FY
Kim
Center for Excellence in Pulmonary Biology, Division of Pulmonary, Asthma and Sleep Medicine, Department of Pediatrics, Stanford University Medical School, Stanford, California.
Elizabeth A
EA
Barnes
Center for Excellence in Pulmonary Biology, Division of Pulmonary, Asthma and Sleep Medicine, Department of Pediatrics, Stanford University Medical School, Stanford, California.
Lihua
L
Ying
Center for Excellence in Pulmonary Biology, Division of Pulmonary, Asthma and Sleep Medicine, Department of Pediatrics, Stanford University Medical School, Stanford, California.
Chihhsin
C
Chen
Center for Excellence in Pulmonary Biology, Division of Pulmonary, Asthma and Sleep Medicine, Department of Pediatrics, Stanford University Medical School, Stanford, California.
Lori
L
Lee
Center for Excellence in Pulmonary Biology, Division of Pulmonary, Asthma and Sleep Medicine, Department of Pediatrics, Stanford University Medical School, Stanford, California.
Cristina M
CM
Alvira
Center for Excellence in Pulmonary Biology, Division of Pulmonary, Asthma and Sleep Medicine, Department of Pediatrics, Stanford University Medical School, Stanford, California cornfield@stanford.edu.
David N
DN
Cornfield
D000818:Animals; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D002908:Chronic Disease; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D066253:Vascular Remodeling / Q000235:genetics
D019332:Endothelin-1; D008840:Microfilament Proteins; D009124:Muscle Proteins; C058992:Tagln protein, mouse; C051615:transgelin
pulmonary hypertension; smooth muscle cells