Fibroblast growth factor stimulates angiotensin converting enzyme expression in vascular smooth muscle cells. Possible mediator of the response to vascular injury.
Angiotensin converting enzyme (ACE) activity contributes to the vascular response to injury because ACE inhibition limits neointima formation in rat carotid arteries after balloon injury. To investigate the mechanisms by which ACE may contribute to vascular smooth muscle cell (VSMC) proliferation, we studied expression of ACE in vivo after injury and in vitro after growth factor stimulation. ACE activity 14 d after injury was increased 3.6-fold in the injured vessel. ACE expression, measured by immunohistochemistry, became apparent at 7 d in the neointima and at 14 d was primarily in the most luminal neointimal cells. To characterize hormones that induce ACE in vivo, cultured VSMC were exposed to steroids and growth factors. Among steroids, only glucocorticoids stimulated ACE expression with an 8.0 +/- 2.1-fold increase in activity and a 6.5-fold increase in mRNA (30 nM dexamethasone for 72 h). Among growth factors tested, only fibroblast growth factor (FGF) stimulated ACE expression (4.2 +/- 0.7-fold increase in activity and 1.6-fold increase in mRNA in response to 10 ng/ml FGF for 24 h). Dexamethasone and FGF were synergistic at the indicated concentrations inducing 50.6 +/- 12.4-fold and 32.5-fold increases in activity and mRNA expression, respectively. In addition, when porcine iliac arteries were transfected with recombinant FGF-1 (in the absence of injury), ACE expression increased in neointimal VSMC, to the same extent as injured, nontransfected arteries. The data suggest a temporal sequence for the response to injury in which FGF induces ACE, ACE generates angiotensin II, and angiotensin II stimulates VSMC growth in concert with FGF.
Fishel
R S
RS
Department of Medicine, Emory University, Atlanta, Georgia 30322.
Thourani
V
V
Eisenberg
S J
SJ
Shai
S Y
SY
Corson
M A
MA
Nabel
E G
EG
Bernstein
K E
KE
Berk
B C
BC
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000473:pathology; D001158:Arteries / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000494:pharmacology*; D005786:Gene Expression Regulation; D005938:Glucocorticoids; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis*; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D013552:Swine; D014162:Transfection
D005938:Glucocorticoids; D011994:Recombinant Proteins; D005346:Fibroblast Growth Factors; D007703:Peptidyl-Dipeptidase A