EFFECTS OF PEPTIDE VASOCONSTRICTORS ON VESSEL STRUCTURE

The peptide vasoconstrictors angiotensin II an endothelin-1, originall y described as being derived exclusively from the plasma renin-angiote nsin system and vascular endothelium, respectively, have been demonstr ated to be produced independently of these sources. Local tissue angio tensin-generating systems are well documented and endothelin productio n has been demonstrated for a variety of nonendothelial cells, includi ng vascular smooth muscle cells. There is increasing evidence that the se locally produced vasoconstrictor peptides may contribute to blood v essel homeostasis, as well as the development of vascular pathologic c onditions. Results obtained from pharmaceutical intervention in humans and animals of these systems strongly support this hypothesis. In add ition to their vasoconstrictor properties, angiotensin II and endothel in-1 act as potent biologic effectors. In vitro, both vasoconstrictor peptides appear to modulate the activity of autocrine feedback loops i n vascular smooth muscle cells. The activity of these feedback loops i n vivo may represent a central mechanism for regulation and phenotypic differentiation of this cell type. The most well-established autocrin e feedback loops of vascular smooth muscle cells are constituted by pl atelet-derived growth factor and transforming growth factor-beta, both of which are influenced by the action of angiotensin II and endotheli n-1. The effects of the peptide vasoconstrictors on the (auto-) regula ted feedback loops are of long-term structural importance, since both vasoconstrictors (via autocrine growth modulators) may influence the c omposition of the extracellular matrix of vascular smooth muscle cells . This includes effects on the synthesis and secretion of thrombospond in, fibronectin, tenascin, etc. The secretion of extracellular matrix glycoproteins themselves and incorporation into extracellular matrix i n vitro appear to be linked to the activity of the autocrine feedback loops: e.g., stimulation of thrombospondin mRNA results in secretion o f the glycoprotein only in the concomitant presence of exogenous plate let-derived growth factor, whereas the expression of fibronectin and t enascin may be directed by transforming growth factor-beta. The influe nce of angiotensin II and endothelin-1 on vascular smooth muscle cell surface receptor expression may represent a secondary mode of action o f these vasoconstrictor peptides. Endothelin-1, for instance, can rapi dly down-regulate platelet-derived growth factor-alpha receptor mRNA a nd both angiotensin II and endothelin-1, via induction of transforming growth factor-beta, may interrupt the platelet-derived growth factor based autocrine feedback loop. In vivo, the highly complex interaction s between local and systemic vasoconstrictor production, autoregulated feedback loops, and extracellular matrix (which also serves as a rese rvoir for growth and differentiation modulators) are central to vessel homeostasis. Disturbance of balance in the normal vessel and a sustai ned loop of autocrine stimulation induced by local vasoconstrictor pep tide overproduction may represent key events in the establishment or p erpetuation of vessel pathologic changes.