Caveolin-1 Plays a Crucial Role in Inhibiting Neuronal Differentiation of Neural Stem/Progenitor Cells via VEGF Signaling-Dependent Pathway

Abstract

In the present study, we aim to elucidate the roles of caveolin-1(Cav-1), a 22 kDa protein in plasma membrane invaginations, in modulating neuronal differentiation of neural progenitor cells (NPCs). In the hippocampal dentate gyrus, we found that Cav-1 knockout mice revealed remarkably higher levels of vascular endothelial growth factor (VEGF) and the more abundant formation of newborn neurons than wild type mice. We then studied the potential mechanisms of Cav-1 in modulating VEGF signaling and neuronal differentiation in isolated cultured NPCs under normoxic and hypoxic conditions. Hypoxic embryonic rat NPCs were exposed to 1% O2 for 24 h and then switched to 21% O2 for 1, 3, 7 and 14 days whereas normoxic NPCs were continuously cultured with 21% O2. Compared with normoxic NPCs, hypoxic NPCs had down-regulated expression of Cav-1 and up-regulated VEGF expression and p44/42MAPK phosphorylation, and enhanced neuronal differentiation. We further studied the roles of Cav-1 in inhibiting neuronal differentiation by using Cav-1 scaffolding domain peptide and Cav-1-specific small interfering RNA. In both normoxic and hypoxic NPCs, Cav-1 peptide markedly down-regulated the expressions of VEGF and flk1, decreased the phosphorylations of p44/42MAPK, Akt and Stat3, and inhibited neuronal differentiation, whereas the knockdown of Cav-1 promoted the expression of VEGF, phosphorylations of p44/42MAPK, Akt and Stat3, and stimulated neuronal differentiation. Moreover, the enhanced phosphorylations of p44/42MAPK, Akt and Stat3, and neuronal differentiation were abolished by co-treatment of VEGF inhibitor V1. These results provide strong evidence to prove that Cav-1 can inhibit neuronal differentiation via down-regulations of VEGF, p44/42MAPK, Akt and Stat3 signaling pathways, and that VEGF signaling is a crucial target of Cav-1. The hypoxia-induced down-regulation of Cav-1 contributes to enhanced neuronal differentiation in NPCs.

Caveolin‐1 regulates neural differentiation of rat bone mesenchymal stem cells into neurons by modulating Notch signaling

“…Caveolin‐1 KO mice exhibit signs of premature neuronal aging and degeneration in the hippocampus, which is similar to what is found in AD; thus, down‐regulation of Cav‐1 may accelerate aging and neurodegeneration (Head et al, 2010). Previous studies have shown that overexpression of caveolin‐1 can promote astroglial differentiation of NPCs, which enhances the Notch signaling pathway (Li et al, 2011a,b). The Notch signaling pathway is highly conserved and plays a crucial role in regulating stem cell proliferation, differentiation, apoptosis, neurogenesis and neuronal differentiation (Liu et al, 2010).…”

Inverse Correlation between Caveolin-1 Expression and Clinical Severity in Psoriasis Vulgaris

“…In contrast, cav-1 inhibits the activity of flk-1, the receptor of VEGF, potently inhibiting VEGF-dependent angiogenesis. 21 In addition, vasodilatation and increased permeability of blood vessels, mediated by nitric oxide, constitutes an important mechanism for angiogenesis. Nitric oxide synthase (NOS) in vascular endothelial cells is located within caveolae and the caveolin scaffolding domain of cav-1 can combine with NOS making it inactive and, thereby, inhibiting angiogenesis.…”

Hypoxic Conditioned Medium from Rat Cerebral Cortical Cells Enhances the Proliferation and Differentiation of Neural Stem Cells Mainly through PI3-K/Akt Pathways

“…VEGF secretion promotes the self-renewal of NSCs and brain development, and it has been found to confer protection from cerebral ischemia [22]. Previous reports have suggested that infusion of VEGF into the lateral ventricle increases neurogenesis by promoting survival of newborn neurons and NSCs [23], [24].…”