PEPTIDE VASOCONSTRICTORS, VESSEL STRUCTURE, AND VASCULAR SMOOTH-MUSCLE PROLIFERATION

The peptide vasoconstrictors angiotensin II (Ang II) and endothelin-1 (ET-1), originally thought to derive exclusively from the plasma renin -angiotensin system and vascular endothelium, respectively, have been demonstrated to be produced independently of such sources. Local tissu e angiotensin-generating systems are well documented, and endothelin p roduction has been demonstrated for a variety of nonendothelial cells, including vascular smooth-muscle cells (VSMC). There is increasing ev idence from in vitro studies that local production of these vasoconstr ictor peptides may contribute to blood vessel homeostasis and the deve lopment of vascular pathologies. Results obtained from pharmaceutical intervention in humans and animals of these systems strongly support t his hypothesis. In addition to their vasoconstrictor properties, Ang I I and ET-1 act as potent biological effectors. In vitro, both vasocons trictor peptides appear to modulate the activity of autocrine feedback loops in VSMC. The activity of these feedback loops in vivo may repre sent a central mechanism for regulation and phenotypic differentiation of this cell type. The best-recognized autocrine feedback loops of VS MC are constituted by platelet-derived growth factor and transforming growth factor-beta, both of which are influenced by the action of Ang II and ET- 1. Because both vasoconstrictors (via their induction of au tocrine growth modulators) may influence the composition of the extrac ellular matrix of VSMC, the effects of the peptide vasoconstrictors on the (auto-) regulated feedback loops are of long-term structural impo rtance. Ang II and ET-1 promote the synthesis and secretion of the gly coproteins thrombospondin, fibronectin, and tenascin. The secretion of these extracellular matrix glycoproteins and their incorporation into extracellular matrix in vitro and in vivo appear to be linked to the activity of the autocrine feedback loops. For example, stimulation of thrombospondin mRNA expression by vasoconstrictor peptides results in secretion of the glycoprotein only in the concomitant presence of exog enous platelet-derived growth factor, whereas the eventual secretion o f fibronectin and tenascin may be directed by transforming growth fact or-beta. A secondary mode of action of Ang II and ET-1 concerns their effects on VSMC surface receptor expression. ET-1, for example, can ra pidly downregulate platelet-derived growth factor alpha-receptor mRNA, and both Ang II and ET-1, possibly via induction of transforming grow th factor-beta, may interrupt the platelet-derived growth factor-based autocrine feedback loop. In vivo, the highly complex interactions amo ng local and systemic vasoconstrictor production, autoregulated feedba ck loops, and extracellular matrix (which also serves as a reservoir f or growth and differentiation modulators) are central to vessel homeos tasis. A disturbance in the normal vessel and a sustained loop of auto crine stimulation induced by local vasoconstrictor peptide overproduct ion may represent a key event in the establishment and/or perpetuation of vessel pathologies.