The role of pulsatile flow in controlling microvascular retinal endothelial and pericyte cell apoptosis and proliferation

AIMS: Aberrant retinal blood flow is a hallmark of various retinopathies and may be a causative factor in the pathology associated with these conditions. We examined the effects of pulsatile flow on bovine retinal endothelial cell (BREC) and bovine retinal pericyte (BRP) apoptosis and proliferation.

METHODS AND RESULTS: Co-cultured BRECs and BRPs were exposed to low (0.3 mL/min) or high (25 mL/min) pulsatile flow for 72 h using a perfused transcapillary culture system. Pulsatile flow increased BREC nitric oxide synthase (eNOS) and cyclooxygenase-2 (COX-2) expression and activity concomitant with a significant decrease in pre-pro-endothelin-1 (ET-1) mRNA and peptide. BREC apoptosis was significantly attenuated following exposure to high flow. The inhibition of NOS, COX, and ET receptors significantly reduced the pro-survival effects of flow on BREC. In contrast, BRP apoptosis was significantly enhanced following exposure to high flow. The inhibition of COX and ET receptors significantly attenuated the high flow-induced increase in BRP apoptosis when compared with untreated controls. Treatment of static BREC with NO donor (S-nitroso-N-acetylpenicillamine, SNAP), ET-1, or iloprost inhibited serum deprivation-induced apoptosis, whereas treatment of BRP with ET-1 and iloprost, but not SNAP, was ineffective. High pulsatile flow decreased BRP proliferation, in the absence of any changes in BREC proliferation.

CONCLUSION: Increased pulsatile flow promotes BREC survival and enhances BRP apoptosis through the activation of endothelial-derived vasoactive substances. Altered pulsatile flow does not alter BREC proliferation in co-culture with BRP, whereas BRP proliferation was significantly decreased at high flow rates. These interactions have important implications for vessel growth and regression during retinal vascular pathogenesis.