Hypercapnia prevents neovascularization via nitrative stress.
Neovascularization after an ischemic insult is a beneficial attempt to salvage the injured tissue. Yet, despite the production of angiogenic factors within ischemic tissues, compensatory growth of new vessels fails to provide adequate vascularization. Thus, we hypothesized that local factors counter efficient revascularization. Whereas ischemia is often considered to be synonymous with an oxygen deficit, it is also associated with a concomitant local elevation of carbon dioxide (CO2). Although studies suggest that hypercapnia impacts tissue neovascularization, its significance relative to the abundantly described effects of hypoxia and its underlying mechanisms have yet to be elucidated. Therefore, we investigated the effects of hypercapnia on blood vessel growth in models of developmental and ischemic neovascularization. Acute and prolonged CO2 exposure inhibited developmental neovascularization of the rodent retina, as well as revascularization of the ischemic retina. Hypercapnia induced early increases in endothelial nitric oxide synthase and nitrative stress, associated with astrocyte impairment and endothelial cell death, as well as downregulation of the proangiogenic prostaglandin E2 receptor EP3. These results establish a previously unexplored means by which hypercapnia hinders efficient neovascularization, a mechanism that may contribute to ischemic tissue injury.
Checchin
Daniella
D
Department of Pediatrics, Department of Ophthalmology, and Department of Pharmacology, Research Center, Hôpital Ste. Justine, Montreal, QC, Canada H3T 1C5.
Sennlaub
Florian
F
Sirinyan
Mirna
M
Brault
Sonia
S
Zhu
Tang
T
Kermorvant-Duchemin
Elsa
E
Hardy
Pierre
P
Balazy
Michael
M
Chemtob
Sylvain
S
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D016923:Cell Death; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006935:Hypercapnia; D007511:Ischemia / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D009566:Nitrates / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors / Q000378:metabolism; D058308:Receptors, Prostaglandin E, EP3 Subtype; D012160:Retina / Q000254:growth & development; D015861:Retinal Neovascularization / Q000378:metabolism; D012171:Retinal Vessels / Q000378:metabolism
D009566:Nitrates; D026361:Reactive Nitrogen Species; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D052250:Nitric Oxide Synthase Type III