Extracellular Environment-Controlled Angiogenesis, and Potential Application for Peripheral Nerve Regeneration.

Shingo Saio,Hirofumi Hohjoh,Yuki Tamura,Kanna Konishi,Ken-Ichi Mizutani,Hiroshi Hasegawa,Masamitsu Ichihashi,Teruaki Masutani,Arunasiri Iddamalgoda

doi:10.3390/ijms222011169

Abstract

Endothelial cells acquire different phenotypes to establish functional vascular networks. Vascular endothelial growth factor (VEGF) signaling induces endothelial proliferation, migration, and survival to regulate vascular development, which leads to the construction of a vascular plexuses with a regular morphology. The spatiotemporal localization of angiogenic factors and the extracellular matrix play fundamental roles in ensuring the proper regulation of angiogenesis. This review article highlights how and what kinds of extracellular environmental molecules regulate angiogenesis. Close interactions between the vascular and neural systems involve shared molecular mechanisms to coordinate developmental and regenerative processes. This review article focuses on current knowledge about the roles of angiogenesis in peripheral nerve regeneration and the latest therapeutic strategies for the treatment of peripheral nerve injury.

Highlights

The mammalian Vascular endothelial growth factor (VEGF) family members include VEGF-A, B, C, D, E, and placental grTohwethmfaacmtomr. aTlhieasne VprEotGeiFnsfahmavielydimffeermenbt ebrinsdiinncgluafdfieniVtieEsGfoFr-Ath,reBe,tCyr,oDsin, eEk, iannasde placental growretchepftaorcst:oVr.ETGhFerseecepprtoorte1in(VsEhGaFvRe1,dFifltf1e)r,eVnEtGbFinR2di(nKgDRaf/Ffilnk-i1ti)e, sanfdorVtEhGreFeR3ty(rFolts4i)ne kinase rece[p6t,7o]r. sM: uVlEtipGleFmreacjoerpatnogri1og(eVnEicGpFroRc1e,ssFelst1a)r,eVgeEnGerFaRte2d(bKyDsiRg/naFllikng-1i)n,vaonlvdinVgEVGEFGRF3-A(Flt4) [6,7]
Recent studies have shown that the tip and stalk phenotypes are not permanent once acquired, but they are dynamically switched throughout angiogenesis [9,10]
extracellular matrix (ECM)-bound VEGF elicits a prolonged activation of VEGFR2 and stimulates angiogenesis, mediated by Integrin signaling, indicating the existence of specific components within the ECM that sustain angiogenesis [17]

Summary

Angiogenesis in Peripheral Axon Regeneration

The development of the vascular and nervous systems is guided by similar signaling pathways [34,35]. It remains unknown which endothelial cell-derived signaling molecules are important for axon regeneration To identify those molecules, we examined the change in expression of secreted factors in injured mouse sciatic nerves induced by cediranib, a VEGFR2 inhibitor. Inhibition of angiogenesis prevents invasion of Schwann cells into the conduit and axon regeneration [45,46,47], while implantation of a vascular nerve conduit, or cultured human umbilical vein endothelial cells with a tube-like structure in collagen hydrogel, promotes peripheral nerve regeneration [48,49] In addition to their function as a guiding structure for Schwann cells and an angiocrine source of secreted factors, the new blood vessels in the conduit support axon regeneration by regulating T lymphocytes. T lymphocyte accumulation, induced by newly formed blood vessels, might play an important role in spontaneous repair

Vascularization Strategies for Peripheral Nerve Regeneration

Concluding Remarks and Perspectives