Critical role of caveolin-1 in ocular neovascularization and multitargeted antiangiogenic effects of cavtratin via JNK

Abstract

Ocular neovascularization is a devastating pathology of numerous ocular diseases and is a major cause of blindness. Caveolin-1 (Cav-1) plays important roles in the vascular system. However, little is known regarding its function and mechanisms in ocular neovascularization. Here, using comprehensive model systems and a cell permeable peptide of Cav-1, cavtratin, we show that Cav-1 is a critical player in ocular neovascularization. The genetic deletion of Cav-1 exacerbated and cavtratin administration inhibited choroidal and retinal neovascularization. Importantly, combined administration of cavtratin and anti-VEGF-A inhibited neovascularization more effectively than monotherapy, suggesting the existence of other pathways inhibited by cavtratin in addition to VEGF-A. Indeed, we found that cavtratin suppressed multiple critical components of pathological angiogenesis, including inflammation, permeability, PDGF-B and endothelial nitric oxide synthase expression (eNOS). Mechanistically, we show that cavtratin inhibits CNV and the survival and migration of microglia and macrophages via JNK. Together, our data demonstrate the unique advantages of cavtratin in antiangiogenic therapy to treat neovascular diseases.

Role of Caveolin-1 in Diabetes and Its Complications

“…They found that the combined administration of cavtratin and anti-VEGF-A (the usual treatment for DR) inhibited neovascularization more effectively than monotherapy. Cavtratin exerts its effect by downregulating eNOS expression and the platelet-derived growth factor-B (PDGF-B) in vivothrough the JNK pathway [213]. These two factors play important roles in pathological angiogenesis [214,215].…”

Neuroretinal-derived caveolin-1 promotes endotoxin-induced inflammation in the murine retina

“…In the retina, Cav1 affects important visual processes such as phagolysosomal digestion of photoreceptor outer segments by the retinal pigment epithelium (RPE) (16), maintenance of retinal vascular blood-retinal-barrier integrity (17)(18)(19), and retinal neovascularization (20). We and others have also implicated Cav1 function specifically in retinal inflammation and immune response modulation (21)(22)(23).…”

Dimethylarginine dimethylaminohydrolase-1 contributes to exercise-induced cardiac angiogenesis in mice

“…Chen demonstrated the primary colocalization of DDAH1 and Caveolin-1 in the endothelium of cardiac microvessels (18). In fact, Caveolin-1 is mainly expressed in endothelial cells (34). It is conceivable that similar localization of DDAH1 and Caveolin-1 substantiates the same function in regulating cardiac angiogenesis.…”