Inhibition of ocular neovascularization by hedgehog blockade.
Ocular neovascularization associated with proliferative diabetic retinopathy and age-related macular degeneration is the leading cause of severe visual loss in adults in developed countries. Physiological and pathological retinal angiogenesis may occur independently in postnatal life through the complex activation of pro- and antiangiogenic pathways. We report that the Sonic hedgehog (Shh) pathway is activated in the retina in animal models of retinal and choroidal neovascularization. We show that pharmacological inhibition of the Shh signaling pathway significantly reduces physiological retinal angiogenesis and inhibits pathological vascularization in both models. Under retinal hypoxic conditions, inhibition of the Shh pathway results in reduction of vascular endothelial growth factor (VEGF) level, along with that of Patched-1 (Ptch1), a canonical Shh target, thus placing Shh activation upstream of VEGF in experimental retinal neovascularization. Our data demonstrate the requirement of the Shh pathway for retinal angiogenesis and its inhibition as a potential therapeutic strategy targeting ocular neovascular disease.
Surace
Enrico M
EM
Telethon Institute of Genetics and Medicine, 80131 Naples, Italy; S.E.M.M. - European School of Molecular Medicine - Naples site, Italy.
Balaggan
Kamaljit S
KS
Tessitore
Alessandra
A
Mussolino
Claudio
C
Cotugno
Gabriella
G
Bonetti
Ciro
C
Vitale
Aniello
A
Ali
Robin R
RR
Auricchio
Alberto
A
D000818:Animals; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D012160:Retina / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D015854:Up-Regulation; D014704:Veratrum Alkaloids / Q000494:pharmacology
D053823:Hedgehog Proteins; D014704:Veratrum Alkaloids; C000541:cyclopamine