A number of receptors and their ligands first shown to regulate axon guidance now appear to regulate angiogenesis as well. These pairs include the semaphorins (SEMA) and their receptors, the neuropilins (NRPs). There are two NRP genes encoding NRP1 and NRP2. NRPs are cell surface glycoprotein first shown to be receptors for the family of chemorepulsive proteins that mediate axon guidance. Our lab cloned NRPs as receptors for VEGF, thus demonstrating that NRPs are also regulators of angiogenesis, besides axon guidance. One of the class3 semaphorins, SEMA3F, is a potent inhibitor of tumor angiogenesis, tumor progression and metastasis. SEMA3F collapses the F-actin cytoskeleton very rapidly. Spreading, contractility and migration are quickly inhibited, a possible mechanism explaining the anti-tumor cell activity. Analysis of the collapse pathway indicates that this pathway in endothelial and tumor cells mimics the mechanisms of axonal growth cone collapse. To begin the pathway, SEMA3F binds NRPs and plexin to form a complex. Important features in the pathway are that SEMA3F inhibits RhoA by activation of p190RhoGAP; RhoA is responsible for stress fiber formation and cytoskeleton structure. Furthermore, due to RhoA inactivation, cofilin becomes dephosphorylated and is activated to depolymerize and sever F-actin cytoskeleton proteins, leading to collapse. Glioblastoma is a fatal disease characterized by tumor cell spreading and migrating within the brain. SEMA 3F is a potent inhibitor of U87MG glioma cell migration and adhesion. Accordingly, the effects of SEMA3F on glioma cells implanted orthotopically in the brain in a mouse model will be examined to determine whether spread of the cancer can be diminished.
In another study aimed at examining blood vessel and neuron interactions in dorsal root ganglia (DRG), it was found that VEGF is expressed by neurons and satellite cells, but not by endothelial cells or pericytes. On the other hand, the tyrosine kinase VEGF receptor, VEGFR-2, is robustly expressed by endothelial cells throughout the extensive DRG capillary network, but is not found at either the transcript or protein level in sensory neurons or other non-endothelial cells of the DRG. Inhibition of VEGFR-2 signaling rapidly disrupts the connectivity, branching, and structural integrity of the capillary network of embryonic DRG. These results are molecular evidence that these two processes, axon guidance and angiogenesis are connected at a molecular level.
