Tetraspanin18 regulates angiogenesis through VEGFR2 and Notch pathways

Abstract

The VEGF pathway is critically required for vasculogenesis, the formation of the primary vascular network. It is also required for angiogenesis resulting in sprouting and pruning of vessels to generate mature arborizing structures. The Notch pathway is essential for arterial–venous specification and the maturation of nascent vessels. We have determined that Tspan18, a member of the Tetraspanin family, is expressed in developing vessels but not in mature vasculature in zebrafish and mouse wound healing. Moreover, reduction at Tspan18 level resulted in aberrant vascular patterning, impaired vessel stability and defective arterial–venous specification. Tspan18 deficiency reduced VEGF, VEGFR2, Notch3 and EphrinB2, and increased EphB4, VEGFR3, Semaphorin3, Neuropilin and PlexinD1 expression. Furthermore, vascular defects of Tspan18 deficiency could be rescued by ectopic expression of VEGFR2 and Notch, but not by knockdown of Semaphorin or Plexin. Functional studies showed that knockdown of Tspan18 led to reduced endothelial cell migration, invasion and tube formation. Tspan18 has dynamic expression, regulates vascular development and maturation in the embryo with re-expression in adult life in wound healing.

Liver Endothelial Heg Regulates Vascular/Biliary Network Patterning and Metabolic Zonation Via Wnt Signaling

“…Other proteins, such as BMP4, BMPER, Dll1, Edn1, and Tspan18, have all been shown to promote angiogenesis and vascular patterning. 47 , 48 More investigations are required to identify what are the critical downstream signals that mediate the function of Heg in regulating liver vascular patterning.…”

Notch signalling in healthy and diseased vasculature

“…More mechanistic insights into the VEGF–Notch–Eph/ephrin axis for arterial specification have been gained in recent years. It has been shown that tetraspanin 18 regulates both Notch and VEGF signalling during developmental angiogenesis [ 30 ]. Benedito and co-workers [ 31 ] demonstrated that elevated VEGF and Notch levels suppress the cell cycle and promote enrolment of ECs into arteries.…”

Tetraspanin Cd9b plays a role in fertility in zebrafish

“…Tetraspanins are widely expressed in teleosts [ 9 ] but there are no reports of roles in fish fertility. Several tetraspanins have roles during zebrafish development, including pigment cell interactions [ 10 ], hatching [ 11 ], vascularisation [ 12 , 13 ] migrasome formation [ 14 ] and primordium migration [ 15 ]. However, the role of Cd9 in fertilisation has not yet been investigated.…”