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.