Abstract 5753: An Axon-guiding Molecule Semaphorin3E is Critically Involved in Impaired Angiogenesis of Diabetes
The axon-guiding molecules known as semaphorins and their specific receptors (plexins) regulate the vascular pattern and play an important role in development of the vascular network during embryogenesis. However, it remains unclear whether these molecules are involved in postnatal angiogenesis. Here we report that semaphorin3E (Sema3E), one of the class 3 semaphorins, and its specific receptor plexinD1 inhibit angiogenesis in adults. Sema3E inhibited cell growth and tube formation by suppressing the vascular endothelial growth factor (VEGF) signaling pathway. Expression of Sema3E and plexinD1 was markedly up-regulated in ischemic limbs of mice, and inhibition of this pathway by introduction of the plexinD1-Fc gene or disruption of Sema3E led to significant improvement of revascularization. We also found that Sema3E-deficient mice showed better blood recovery and a larger vessel area in their ischemic limbs than wild-type mice, suggesting that Sema3E/plexinD1 negatively regulate postnatal angiogenesis. Next, we identified a putative binding element of p53, the tumor suppressor protein, within the promotor region of the Sema3E gene, and found that hypoxia up-regulated Sema3E expression by activating p53 in endothelial cells. Consistent with our in vitro data, up-regulation of Sema3E expression was abolished in the ischemic limbs of p53-deficient mice, suggesting that an increase of p53 promotes Sema3E expression in ischemic tissue and thus inhibits blood flow recovery. It has been reported that angiogenic response to ischemia is attenuated in diabetes. We found that expression of p53 was increased in diabetic mice and this increase was further enhanced by ischemia. Likewise, expression levels of Sema3E were significantly higher in diabetic mice than in control mice. Consequently, blood flow recovery after VEGF treatment was impaired in diabetic mice compared with VEGF-treated control mice. These changes were effectively reversed by additional introduction of the plexinD1-Fc gene. These results indicate that Sema3E negatively regulates postnatal angiogenesis and suggest that inhibition of Sema3E would be a novel strategy for therapeutic angiogenesis, especially when VEGF treatment is ineffective, such as in the diabetic state.