The role of retinoids and protein kinase C in vascular smooth muscle cell proliferation and function

The structural and functional changes in the arterial wall of humans and animals accompany the development of hypertension and atherosclerosis. Hence, great interest exists in the mechanisms that govern vascular smooth muscle cell contraction and proliferation. Rat aortic rings maintained in organ culture show a significant loss of contractility; whereas, vascular smooth muscle cells in culture quickly dedifferentiate into a secretory phenotype with a marked capacity for proliferation. The addition of all-trans retinoic acid (RA) and retinol to the plasma-containing medium preserved the contractile response of cultured vessels. Removal of endothelium prior to culture abolished these effects. All-trans retinoic acid but not retinol inhibited A7r5 smooth muscle cell growth; whereas, retinol significantly inhibited A7r5 cell growth in the presence of bovine aortic endothelial cells (BAEC). Conditioned medium from BAEC treated with retinol also inhibited A7r5 cell growth and several metabolites of retinol were found released by BAEC in HPLC analysis. A7r5 smooth muscle cells express five PKC isozymes. RA treatment increased the expression of PKCα, δ, and ε. Overexpression of PKCα in A7r5 cells was used to elucidate its role in the regulation of smooth muscle cell differentiation. Overexpressing clones had altered morphology and decreased growth rates. Cell differentiation marker proteins such as vinculin and desmin were not affected by PKCα overexpression; whereas, the expression of smooth muscle-specific a-actin was markedly reduced. These findings suggest that PKCα may regulate growth independently from differentiation. The results suggest that circulating factors, such as retinol and retinoic acid, may be necessary for the maintenance of the differentiated state of smooth muscle. Retinol appears to exert its effects primarily on the endothelium, which in turn secretes stable factors that affect smooth muscle phenotype. The regulatory effect of RA may involve PKC. Individual isoforms of PKC may play different roles in regulating smooth muscle cell proliferation and contraction