Peptide Vasoconstrictors, Vessel Structure, and Vascular Smooth-Muscle Proliferation

Abstract

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 tissue angiotensin-generating systems are well documented, and endothelin production has been demonstrated for a variety of nonendothelial cells, including vascular smooth-muscle cells (VSMC). There is increasing evidence from in vitro studies that local production of these vasoconstrictor peptides may contribute to blood vessel homeostasis and the development of vascular pathologies. Results obtained from pharmaceutical intervention in humans and animals of these systems strongly support this hypothesis. In addition to their vasoconstrictor properties, Ang II and ET-1 act as potent biological effectors. In vitro, both vasoconstrictor peptides appear to modulate the activity of autocrine feedback loops in VSMC. The activity of these feedback loops in vivo may represent a central mechanism for regulation and phenotypic differentiation of this cell type. The best-recognized autocrine feedback loops of VSMC are constituted by platelet-derived growth factor and transforming growth factor-β, both of which are influenced by the action of Ang II and ET-1. Because both vasoconstrictors (via their induction of autocrine growth modulators) may influence the composition of the extracellular matrix of VSMC, the effects of the peptide vasoconstrictors on the (auto-) regulated feedback loops are of long-term structural importance. Ang II and ET-1 promote the synthesis and secretion of the glycoproteins 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 exogenous platelet-derived growth factor, whereas the eventual secretion of fibronectin and tenascin may be directed by transforming growth factor-β. A secondary mode of action of Ang II and ET-1 concerns their effects on VSMC surface receptor expression. ET-1, for example, can rapidly downregulate platelet-derived growth factor α-receptor mRNA, and both Ang II and ET-1, possibly via induction of transforming growth factor-β, may interrupt the platelet-derived growth factor-based autocrine feedback loop. In vivo, the highly complex interactions among local and systemic vasoconstrictor production, autoregulated feedback loops, and extracellular matrix (which also serves as a reservoir for growth and differentiation modulators) are central to vessel homeostasis. A disturbance in the normal vessel and a sustained loop of autocrine stimulation induced by local vasoconstrictor peptide overproduction may represent a key event in the establishment and/or perpetuation of vessel pathologies.