Stimulation of rat vascular smooth muscle cell glycosaminoglycan production by angiotensin II.
Matrix production by smooth muscle cells (SMC) appears to play a major role in the intimal thickening process. Proteoglycans (PG) are the predominant extracellular matrix component of early restenotic lesions. As angiotensin II (A II) has been proposed as a mediator of restenotic process, we hypothesized that A II may directly affect PG synthesis by SMC. SMC were cultured in the presence of [35S]sulfate and angiotensin II, and both the secreted and membrane-bound proteoglycans were analyzed. A II (1 to 100 nM) evoked a dose- and time-dependent increase in both cell- and media-associated PG production, an effect abrogated by the A II receptor antagonist, saralasin. SMC constitutively synthesize small amounts of PG with a molecular mass of 170-250 kDa. After treatment with A II, the abundance of PG is increased, as well as its molecular mass (230-300 kDa). Selective degradation by chondroitinases and heparinase identified chondroitin and dermatan sulfate PG as the predominant form being induced. These results demonstrate that the effect of A II is not general and is specific to certain classes of PGs. In order to further examine the specificity of the A II effect, we compared the synthesis of PG induced by A II with that induced by platelet-derived growth factors AA and BB (PDGF-AA and -BB), insulin-like growth factor I (IGF-I), and tumor necrosis factor alpha (TNF alpha). This comparison demonstrated that the profile of PG induced by A II is different from the other factors examined. Taken together, these data indicate that A II may not only function as a hypertrophic factor for SMC, but in addition may also be a potent modulator of specific PG synthesis by these same cells, which could significantly contribute to the formation of atherosclerotic and restenotic lesions.
Division of Cardiology, Cedars-Sinai Medical Center, UCLA School of Medicine 90048.
W L
WL
Bailey
D W
DW
LaFleur
J S
JS
Forrester
J A
JA
Fagin
B G
BG
Sharifi
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D002807:Chondroitin / Q000096:biosynthesis; D003871:Dermatan Sulfate / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D006025:Glycosaminoglycans / Q000096:biosynthesis*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012504:Saralasin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D006025:Glycosaminoglycans; D010982:Platelet-Derived Growth Factor; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; D003871:Dermatan Sulfate; D007334:Insulin-Like Growth Factor I; D002807:Chondroitin; D012504:Saralasin