Endothelialderived Stimulators Of Smooth Muscle Cell Growth

Endothelial cells have the capacity to secrete several factors that are thought to be involved in the abnormal smooth muscle cell growth seen during atherogenesis and hypertension. As noted previously, the most well studied of these factors is PDGF, so named because it was originally isolated from platelets. PDGF is a dimer, composed of two distinct peptide chains (designated A and B chains), and can be produced as an AB heterodimer or as an AA or BB homodimer. Endothelial cells contain the mRNA for both peptides,112 although the precise form in which PDGF is secreted is unclear. Release of PDGF from the endothelium is regulated by second messengers such as cAMP and activators of protein kinase C; other growth factors including TGF-ft, FGF, and TNF; circulating factors; and locally produced factors such as thrombin.112 A second growth factor made and secreted by endothelial cells is IGF-1,13 which is a progression factor that facilitates movement of cells through the cell cycle but, by itself, is not a particularly strong mitogen. In vitro, it enhances the mitogenic effect of PDGF on smooth muscle.114 IGF-1 production by endothelium has been shown to be regulated by PDGF and has been shown to be a major player in vascular hypertrophy and hyperplasia.115

Other factors made by the endothelium that are able to alter smooth muscle proliferation include interleukin 1 (IL-1), FGF, and endothelin. IL-1 is an inflammatory cytokine that has numerous vascular effects in addition to mitogenesis, including the stimulation of procoagulant activity,116 induction of leukocyte adhesiveness (see below), and inhibition of contraction.117 IL-1 regulates its own expression,118 and, in addition, its production is regulated by TNF-P,163 lipopolysaccharide, and y-interferon.118 As already noted, basic FGF has been detected in endothelial cells17 and acts as a potent smooth muscle mitogen, particularly after denuding injury.61 FGF does not contain the signal peptide that usually provides a mechanism for transporting proteins out of cells and thus may not be secreted by endothelial cells. It is, however, present and stored in the subendothelial matrix and may be released on cell lysis or death.119 FGF released from VSMCs may be particularly important in the growth response induced by injury to the arterial wall after balloon angioplasty. FGF bound to the matrix can be released by heparin and proteinases,120 suggesting that the matrix may serve as a store for rapidly mobilizing this growth factor. Finally, the vasoconstrictor endothelin has also been shown under certain circumstances to act as a smooth muscle mitogen,121 possibly by increasing PDGF-A chain secretion in the smooth muscle cells themselves.

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