Modulation of endothelial cell shape and growth by retinoids.

Physiologic concentrations of retinol (1 X 10(-6) M) caused capillary and aortic endothelial cells (EC) to undergo a morphologic change, characterized by a rounder cell body, increased refractility at cell edges, and longer cytoplasmic processes distributed in a bipolar fashion. Computer image analysis of retinoid-treated EC revealed that both retinoic acid and retinol affected cellular area. Twenty-four hours following retinoic acid treatment, EC occupied a greater area than control (P less than 0.03) or retinol-treated EC (P less than 0.02). By Day 7, however, retinoic acid-treated EC occupied equivalent cellular areas as compared to control cells (P = 0.8). In contrast, by Day 7, retinol-treated EC occupied a smaller cellular area than control (P less than 0.002) or retinoic acid-treated EC (P less than 0.001). Proliferation studies revealed that within the first 72 hr of retinol treatment, basal EC growth was inhibited by 33% and the cells exhibited a lowered responsiveness to basic fibroblast growth factor (bFGF). In contrast, EC treated with retinoic acid and pericytes treated with each of the retinoids were not inhibited. The inhibitory effect of the 72 hr retinol treatment was reversible. Following 3 days exposure to retinol, EC given fresh media without retinoid underwent a population doubling in a subsequent 3-day period. However, in the continued presence of retinol, EC were 100% growth-inhibited. After a 3-day pretreatment with retinol, with or without continued retinol treatment, EC were refractile to the mitogenic action of bFGF in a subsequent 3-day period. These results demonstrate that retinol inhibits the basal and growth factor-stimulated growth of EC and causes a significant shape alteration of EC, supporting our hypothesis that vitamin A may be one of the signals that modify the growth and phenotype of EC.