TY - JOUR
T1 - Injury-Induced Shedding of Extracellular Vesicles Depletes Endothelial Cells of Cav-1 (Caveolin-1) and Enables TGF-β (Transforming Growth Factor-β)-Dependent Pulmonary Arterial Hypertension
AU - Oliveira, Suellen D.S.
AU - Chen, Jiwang
AU - Castellon, Maricela
AU - Mao, Mao
AU - Raj, J. Usha
AU - Comhair, Suzy
AU - Erzurum, Serpil
AU - Silva, Claudia L.M.
AU - Machado, Roberto F.
AU - Bonini, Marcelo G.
AU - Minshall, Richard D.
N1 - Funding Information:
This work was supported, in part, by CTSA (Clinical and Translational Science Award) UL1 TR002003, National Institutes of Health National Heart, Lung, and Blood Institute grants P01 HL60678 and R01 HL71626 (R.D. Minshall), HL60917 and HL115008 (S. Erzurum, S. Comhair), HL125356 and DOD W911NF1510410 (R.M., M.G. Bonini), American Heart Association Grant-in-Aid 13GRNT 16400010 and NIAID (National Institute of Allergy and Infectious Disease) 131267 (M.G. Bonini), and a postdoctoral fellowship from CNPq (The Brazilian National Council for Scientific and Technological Development; Science Without Borders–Brazil) and an award from the American Heart Association and the Circle of Service Foundation (18POST34020037; S.D.S. Oliveira).
Publisher Copyright:
© 2019 © 2019 American Heart Association, Inc. All rights reserved.
PY - 2019/6/1
Y1 - 2019/6/1
N2 - Objective-To determine whether pulmonary arterial hypertension is associated with endothelial cell (EC)-Cav-1 (caveolin-1) depletion, EC-derived extracellular vesicle cross talk with macrophages, and proliferation of Cav-1 depleted ECs via TGF-β (transforming growth factor-β) signaling. Approach and Results-Pulmonary vascular disease was induced in Sprague-Dawley rats by exposure to a single injection of VEGFRII (vascular endothelial growth factor receptor II) antagonist SU5416 (Su) followed by hypoxia (Hx) plus normoxia (4 weeks each-HxSu model) and in WT (wild type; Tie2.Cre-;Cav1lox/lox) and EC-Cav1-/- (Tie2.Cre+;Cav1fl/fl) mice (Hx: 4 weeks). We observed reduced lung Cav-1 expression in the HxSu rat model in association with increased Cav-1+ extracellular vesicle shedding into the circulation. Whereas WT mice exposed to hypoxia exhibited increased right ventricular systolic pressure and pulmonary microvascular thickening compared with the group maintained in normoxia, the remodeling was further increased in EC-Cav1-/- mice indicating EC Cav-1 expression protects against hypoxia-induced pulmonary hypertension. Depletion of EC Cav-1 was associated with reduced BMPRII (bone morphogenetic protein receptor II) expression, increased macrophage-dependent TGF-β production, and activation of pSMAD2/3 signaling in the lung. In vitro, in the absence of Cav-1, eNOS (endothelial NO synthase) dysfunction was implicated in the mechanism of EC phenotype switching. Finally, reduced expression of EC Cav-1 in lung histological sections from human pulmonary arterial hypertension donors was associated with increased plasma concentration of Cav-1, extracellular vesicles, and TGF-β, indicating Cav-1 may be a plasma biomarker of vascular injury and key determinant of TGF-β-induced pulmonary vascular remodeling. Conclusions-EC Cav-1 depletion occurs, in part, via Cav-1+ extracellular vesicle shedding into the circulation, which contributes to increased TGF-β signaling, EC proliferation, vascular remodeling, and pulmonary arterial hypertension.
AB - Objective-To determine whether pulmonary arterial hypertension is associated with endothelial cell (EC)-Cav-1 (caveolin-1) depletion, EC-derived extracellular vesicle cross talk with macrophages, and proliferation of Cav-1 depleted ECs via TGF-β (transforming growth factor-β) signaling. Approach and Results-Pulmonary vascular disease was induced in Sprague-Dawley rats by exposure to a single injection of VEGFRII (vascular endothelial growth factor receptor II) antagonist SU5416 (Su) followed by hypoxia (Hx) plus normoxia (4 weeks each-HxSu model) and in WT (wild type; Tie2.Cre-;Cav1lox/lox) and EC-Cav1-/- (Tie2.Cre+;Cav1fl/fl) mice (Hx: 4 weeks). We observed reduced lung Cav-1 expression in the HxSu rat model in association with increased Cav-1+ extracellular vesicle shedding into the circulation. Whereas WT mice exposed to hypoxia exhibited increased right ventricular systolic pressure and pulmonary microvascular thickening compared with the group maintained in normoxia, the remodeling was further increased in EC-Cav1-/- mice indicating EC Cav-1 expression protects against hypoxia-induced pulmonary hypertension. Depletion of EC Cav-1 was associated with reduced BMPRII (bone morphogenetic protein receptor II) expression, increased macrophage-dependent TGF-β production, and activation of pSMAD2/3 signaling in the lung. In vitro, in the absence of Cav-1, eNOS (endothelial NO synthase) dysfunction was implicated in the mechanism of EC phenotype switching. Finally, reduced expression of EC Cav-1 in lung histological sections from human pulmonary arterial hypertension donors was associated with increased plasma concentration of Cav-1, extracellular vesicles, and TGF-β, indicating Cav-1 may be a plasma biomarker of vascular injury and key determinant of TGF-β-induced pulmonary vascular remodeling. Conclusions-EC Cav-1 depletion occurs, in part, via Cav-1+ extracellular vesicle shedding into the circulation, which contributes to increased TGF-β signaling, EC proliferation, vascular remodeling, and pulmonary arterial hypertension.
KW - TGF-β
KW - caveolin 1
KW - endothelial cells
KW - extracellular vesicles
KW - inflammation
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U2 - 10.1161/ATVBAHA.118.312038
DO - 10.1161/ATVBAHA.118.312038
M3 - Article
C2 - 30943774
AN - SCOPUS:85066511992
SN - 1079-5642
VL - 39
SP - 1191
EP - 1202
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 6
ER -
