Elucidating the Role of Endothelin-2 (ET-2) in Inherited Photoreceptor Degenerations and the Indirect Effects of Systemic ET-2 Loss

Inherited photoreceptor degenerations (IPDs) are the most common monogenic cause of blindness in humans. To discover genes that may influence the risk of death in IPDs, microarray studies were used, and ET-2 was identified as the most differentially expressed transcript. ET-2 mRNA was 32-fold (p0.05), suggesting that the rescue observed in vivo might be due to extraocular mechanisms. Additionally, the expression of ET-2 mRNA from an rAAV5-CBA-ET-2 vector in ET-2-/-; Rd1-/- retinas did not restore PR degeneration (n=6;p>0.05). A survey of the extraocular phenotypes of ET-2 null mice showed them to be hypoxic owing to aberrant lung development, with a loss of normal alveolarization of the lung. Erythropoietin (EPO) levels were 11-fold elevated in the serum of ET-2 null mice (n=7;p<0.05) and retinal vascular endothelial growth factor (VEGF) was increased 4-fold (n=4;p<0.05). To examine the role of hypoxia in PR degeneration and to exclude increased EPO levels as the sole factor accounting for the rescue of mutant PRs in ET-2-/-; Tg(RHO P347S) and ET-2-/-;Rd1-/- mice in vivo, the effect of hypoxia on PR death in Rd1-/- retinal explants was examined. Rd1-/- explants cultured in 6% O2 from PN10 to PN17 showed a 32% rescue of PR death (n=5;p