Induction of pulmonary hypertension by an angiopoietin 1/TIE2/serotonin pathway

被引:107
作者
Sullivan, CC
Du, LL
Chu, D
Cho, AJ
Kido, M
Wolff, PL
Jamieson, SW
Thistlethwaite, PA
机构
[1] Univ Calif San Diego, Div Cardiothorac Surg, San Diego, CA 92103 USA
[2] Vet Affairs Med Ctr, Dept Pathol, La Jolla, CA 92161 USA
[3] Univ Calif San Diego, La Jolla, CA 92161 USA
关键词
D O I
10.1073/pnas.1933740100
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Smooth muscle cell proliferation around small pulmonary vessels is essential to the pathogenesis of pulmonary hypertension. Here we describe a molecular mechanism and animal model for this vascular pathology. Rodents engineered to express angiopoietin 1 (Ang-1) constitutively in the lung develop severe pulmonary hypertension. These animals manifest diffuse medial thickening in small pulmonary vessels, resulting from smooth muscle cell hyperplasia. This pathology is common to all forms of human pulmonary hypertension. We demonstrate that Ang-1 stimulates pulmonary arteriolar endothelial cells through a TIE2 (receptor with tyrosine kinase activity containing IgG-like loops and epidermal growth factor homology domains) pathway to produce and secrete serotonin (5-hydroxytryptamine), a potent smooth muscle mitogen, and find that high levels of serotonin are present both in human and rodent pulmonary hypertensive lung tissue. These results suggest that pulmonary hypertensive vasculopathy occurs through an Ang-1/ TIE2/serotonin paracrine pathway and imply that these signaling molecules may be targets for strategies to treat this disease.
引用
收藏
页码:12331 / 12336
页数:6
相关论文
共 24 条
[1]   Chronic thromboembolism: Diagnosis with helical CT and MR imaging with angiographic and surgical correlation [J].
Bergin, CJ ;
Sirlin, CB ;
Hauschildt, JP ;
Huynh, TV ;
Auger, WR ;
Fedullo, PF ;
Kapelanski, DP .
RADIOLOGY, 1997, 204 (03) :695-702
[2]  
COLBY TV, 1997, HISTOLOGY PATHOLOGIS, P433
[3]   Disruption of the sarcoglycan-sarcospan complex in vascular smooth muscle: A novel mechanism for cardiomyopathy and muscular dystrophy [J].
Coral-Vazquez, R ;
Cohn, RD ;
Moore, SA ;
Hill, JA ;
Weiss, RM ;
Davisson, RL ;
Straub, V ;
Barresi, R ;
Bansal, D ;
Hrstka, RF ;
Williamson, R ;
Campbell, KP .
CELL, 1999, 98 (04) :465-474
[4]   Isolation of Angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning [J].
Davis, S ;
Aldrich, TH ;
Jones, PF ;
Acheson, A ;
Compton, DL ;
Jain, V ;
Ryan, TE ;
Bruno, J ;
Radziejewski, C ;
Maisonpierre, PC ;
Yancopoulos, GD .
CELL, 1996, 87 (07) :1161-1169
[5]  
Davis S, 1999, CURR TOP MICROBIOL, V237, P173
[6]   Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene [J].
Deng, ZM ;
Morse, JH ;
Slager, SL ;
Cuervo, N ;
Moore, KJ ;
Venetos, G ;
Kalachikov, S ;
Cayanis, E ;
Fischer, SG ;
Barst, RJ ;
Hodge, SE ;
Knowles, JA .
AMERICAN JOURNAL OF HUMAN GENETICS, 2000, 67 (03) :737-744
[7]  
Du Lingling, 2003, New England Journal of Medicine, V348, P500, DOI 10.1056/NEJMoa021650
[8]   Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension [J].
Eddahibi, S ;
Humbert, M ;
Fadel, E ;
Raffestin, B ;
Darmon, M ;
Capron, F ;
Simonneau, G ;
Dartevelle, P ;
Hamon, M ;
Adnot, S .
JOURNAL OF CLINICAL INVESTIGATION, 2001, 108 (08) :1141-1150
[9]   Blood vessel formation: What is its molecular basis? [J].
Folkman, J ;
DAmore, PA .
CELL, 1996, 87 (07) :1153-1155
[10]  
GOMEZFOIX AM, 1992, J BIOL CHEM, V267, P25129