Abstract
Vascular endothelial growth factors (VEGFs) include five molecules (VEGF-A, -B, -C, -D, and placental growth factor), and have various roles that crucially regulate cellular functions in many kinds of cells and tissues. Intracellular signal transduction induced by VEGFs has been extensively studied and is usually initiated by their binding to two classes of transmembrane receptors: receptor tyrosine kinase VEGF receptors (VEGF receptor-1, -2 and -3) and neuropilins (NRP1 and NRP2). In addition to many established results reported by other research groups, we have previously identified small G proteins, especially Ras homologue gene (Rho) and Ras-related protein (Rap), as important mediators of VEGF-A-stimulated signaling in cancer cells as well as endothelial cells. This review article describes the VEGF-A-induced signaling pathways underlying diverse cellular functions, including cell proliferation, migration, and angiogenesis, and the involvement of Rho, Rap, and their related molecules in these pathways.
Highlights
Vascular endothelial growth factors (VEGFs) are secreted glycoproteins
There are more than 150 small G proteins [11], of which we focus on the Ras homologue gene (Rho) and Ras-related protein (Rap) families
Conditional knockout of Rac1 under control of the Tie-2 promoter in mice causes embryonic lethality with severe defects in the development of major blood vessels [30]. These results suggest that Rac1 plays a central role in endothelial cell proliferation, migration, permeability, and angiogenesis in response to VEGF-A
Summary
Vascular endothelial growth factors (VEGFs) are secreted glycoproteins. There are five VEGF family members in mammals: VEGF-A through D, and placental growth factor (PlGF) [1]. Conditional knockout of Rac under control of the Tie-2 promoter in mice causes embryonic lethality with severe defects in the development of major blood vessels [30] These results suggest that Rac plays a central role in endothelial cell proliferation, migration, permeability, and angiogenesis in response to VEGF-A. Similar to Rac and Cdc, RhoA plays an essential role in vascular endothelial cell functions downstream of VEGF-A and VEGF receptor-2. In parallel, activated Src induces the activation of RhoA to cause actin bundle rearrangement (stress fiber formation), which robustly increases contractile force, resulting in the retraction (shrinkage) of endothelial cells and the disruption of intercellular junctions. The formation of stress fibers to facilitate cellular contraction is crucial for endothelial cell migration This phenomenon is tightly regulated by VEGF-A–VEGF receptor-2-induced activation of the RhoA pathway [40]. These results imply a contribution of RhoA to VEGF-A-initiated proliferative signals
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
