Awa. Hahn et al., PEPTIDE VASOCONSTRICTORS, VESSEL STRUCTURE, AND VASCULAR SMOOTH-MUSCLE PROLIFERATION, Journal of cardiovascular pharmacology, 22, 1993, pp. 190000037-190000043
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.