| Hypercapnia, elevated carbon dioxide (CO2), is an established vasodilator, is present during ischemic episodes, and is a risk factor for retinopathy of prematurity, a disease of the retinal vasculature. Retinopathy of prematurity is an ischemic retinopathy, which like other ischemic pathologies, regresses with the reparation of existing blood vessels and the formation of new ones. However, the potential role of CO2 in this process has been relatively overlooked, particularly in comparison to the numerous studies examining hypoxia in ischemia. Therefore, the central aim of this work was to elucidate how hypercapnia affects the retinal vasculature, impacting blood flow and neovascularization.;Collectively the data suggests that CO2, despite typically being considered rather innocuous, can be detrimental in certain circumstances. In the neonatal retina hypercapnia inappropriately augments RBF via a sequence of events, culminating in a free radical-mediated stress that impairs key players required for proper neovascularization. These findings impart several novel avenues for future research as not only do they improve our understanding of developmental, pathological, and therapeutic retinal neovascularization, but they convey a seminal perspective of CO2 creating a framework within which to examine hypercapnia in other tissues.;Retinal blood flow (RBF) studies in hypercapnia-exposed piglets, and rodent models of CO2-induced retinopathy, demonstrate that hypercapnia leads to initial increases in prostaglandin (PG) E2, which mediates an early elevation in RBF, and subsequently augments the endothelial nitric oxide (NO) synthase expression and activity responsible for a later rise in RBF. Ex vivo retinal organ bath experiments and in vitro studies on retinal endothelial cells (ECs) confirmed these findings and revealed that PGE2 increases via EC calcium entry triggered by hypercapnia's accompanying acidosis. While the elevation in RBF creates an oxidative stress, which is detrimental in and of itself, the NO exacerbates this by generating a nitrative stress, resulting in diminished neovascularization. The mechanisms implicated in this include: (1) an altered EC/astrocyte interaction vital to vascularization; (2) the downregulation of the angiogenic PGE 2 receptor EP3; and (3) the direct loss of ECs and microglia, the latter of which we unveil for the first time to have a role in blood vessel development. |
