ANGIOTENSIN-II AND ITS EFFECT ON THE STRUCTURE OF THE VESSELS

The peptide vasoconstrictor angiotensin II (Ang II), originally described as deriving exclusively from the plasma renin angiotensin system, has now been demonstrated to be produced independently of such sources. Local tissue angiotensin-generating systems are well documented. There is increasing evidence that these locally produced vasoconstrictor peptides may contribute to blood vessel homeostasis, as well as the development of vascular pathologies. Results obtained from pharmaceutical intervention in these systems in humans and animals strongly support this hypothesis. In addition to its vasoconstrictor properties, Ang II acts as a potent biological effector. In vitro both vasoconstrictor peptides appear to modulate the activity of autocrine feedback loops in vascular smooth muscle cells. The activity of these feedback loops in vivo may represent a central mechanism for regulation and phenotypic differentiation of this cell type. The most well-established autocrine feedback loops of vascular smooth muscle cells are constituted by platelet-derived growth factor and transforming growth factor-beta, both of which are influenced by the action of angiotensin II. The effects of the peptide vasoconstrictors on the (auto) regulated feedback loops are of long-term structural importance since both vasoconstrictors (via autocrine growth modulators) may influence the composition of the extracellular matrix of vascular smooth muscle cells. This includes effects on the synthesis and secretion of thrombospondin, fibronectin, tenascin, etc. The secretion of extracellular matrix glycoproteins themselves and incorporation into extracellular matrix in vitro appears to be linked to the activity of the autocrine feedback loops: e.g., stimulation of thrombospondin mRNA results in secretion of the glycoprotein only in the concomitant presence of exogenous platelet-derived growth factor, whereas the expression of fibronection and tenascin may be directed by transforming growth factor-beta. In vivo, the highly complex interactions between local/systemic vasoconstrictor production, autoregulated feedback loops and extracellular matrix (which also serves as a reservoir for growth and differentiation modulators) is central to vessel homeostasis. Disturbance of its balance 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.