Reexpression of caveolin-1 in endothelium rescues the vascular, cardiac, and pulmonary defects in global caveolin-1 knockout mice.
Caveolin-1 (Cav-1) is the principal structural component of caveolae organelles in smooth muscle cells, adipocytes, fibroblasts, epithelial cells, and endothelial cells (ECs). Cav-1-deficient (Cav-1 knockout [KO]) mice are viable and show increases of nitric oxide (NO) production in vasculature, cardiomyopathy, and pulmonary dysfunction. In this study, we generated EC-specific Cav-1-reconstituted (Cav-1 RC) mice and reexamined vascular, cardiac, and pulmonary phenotypes. Cav-1 KO pulmonary arteries had decreased smooth muscle contractility and increased endothelial NO synthase activation and hypotension; the latter two effects were rescued completely in Cav-1 RC mice. Cav-1 KO mice exhibited myocardial hypertrophy, pulmonary hypertension, and alveolar cell hyperproliferation caused by constitutive activation of p42/44 mitogen-activated protein kinase and Akt. Interestingly, in Cav-1 RC mice, cardiac hypertrophy and pulmonary hypertension were completely rescued, whereas alveolar hyperplasia was partially recovered because of the lack of rescue of Cav-1 in bronchiolar epithelial cells. These results provide clear physiological evidence supporting the important role of cell type-specific Cav-1 expression governing multiple phenotypes in the vasculature, heart, and lung.
Murata
Takahisa
T
Department of Pharmacology and Program in Vascular Cell Signaling and Therapeutics, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06511.
Lin
Michelle I
MI
Huang
Yan
Y
Yu
Jun
J
Bauer
Phillip Michael
PM
Giordano
Frank J
FJ
Sessa
William C
WC
D000818:Animals; D001808:Blood Vessels / Q000378:metabolism* / Q000473:pathology; D001835:Body Weight; D051242:Caveolin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003094:Collagen / Q000096:biosynthesis; D004727:Endothelium / Q000378:metabolism; D005786:Gene Expression Regulation; D006330:Heart Defects, Congenital / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008171:Lung Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010641:Phenotype; D015398:Signal Transduction
D051242:Caveolin 1; D003094:Collagen; D052250:Nitric Oxide Synthase Type III