betaPix plays a dual role in cerebral vascular stability and angiogenesis, and interacts with integrin alphavbeta8
- Authors
- Liu, J., Zeng, L., Kennedy, R.M., Gruenig, N.M., and Childs, S.J.
- ID
- ZDB-PUB-120727-28
- Date
- 2012
- Source
- Developmental Biology 363(1): 95-105 (Journal)
- Registered Authors
- Childs, Sarah J., Liu, Jing, Zeng, Lei
- Keywords
- βPix, integrin, Git1, angiogenesis, vascular stability, zebrafish
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Blood Vessels/embryology
- Blood Vessels/metabolism*
- Brain/blood supply
- Brain/embryology
- Brain/metabolism
- Cell Proliferation
- Cerebral Hemorrhage/embryology
- Cerebral Hemorrhage/genetics
- Cerebrovascular Circulation/genetics
- Endothelial Cells/metabolism
- GTPase-Activating Proteins/genetics
- GTPase-Activating Proteins/metabolism
- Gene Expression Regulation, Developmental
- Gene Knockdown Techniques
- Green Fluorescent Proteins/genetics
- Green Fluorescent Proteins/metabolism
- Guanine Nucleotide Exchange Factors/genetics*
- Guanine Nucleotide Exchange Factors/metabolism
- Guanine Nucleotide Exchange Factors/physiology
- Immunohistochemistry
- In Situ Hybridization
- Integrins/genetics*
- Integrins/metabolism
- Mutation
- Neovascularization, Physiologic/genetics*
- Neovascularization, Physiologic/physiology
- Protein Binding
- Reverse Transcriptase Polymerase Chain Reaction
- Rho Guanine Nucleotide Exchange Factors
- Zebrafish/embryology
- Zebrafish/genetics
- Zebrafish/metabolism
- Zebrafish Proteins/genetics*
- Zebrafish Proteins/metabolism
- PubMed
- 22206757 Full text @ Dev. Biol.
The growth of new blood vessels by angiogenesis and their stabilization by the recruitment of perivascular mural cells are thought to be two sequential, yet independent events. Here we identify molecular links between both processes through the βPix and integrin αvβ8 proteins. Bubblehead (bbh) mutants with a genetic mutation in βPix show defective vascular stabilization. βPix is a guanine nucleotide exchange factor and scaffold protein that binds many proteins including Git1, which bridges βPix to integrins at focal adhesions. Here we show that the ability of βPix to stabilize vessels requires Git1 binding residues. Knockdown of Git1 leads to a hemorrhage phenotype similar to loss of integrin αv, integrin β8 or βPix, suggesting that vascular stabilization through βPix involves interactions with integrins. Furthermore, double loss of function of βPix and integrin αv shows enhanced hemorrhage rates. Not only is vascular stability impaired in these embryos, but we also uncover a novel role of both βPix and integrin αvβ8 in cerebral angiogenesis. Downregulation of either βPix or integrin αvβ8 results in fewer and morphologically abnormal cerebral arteries penetrating the hindbrain. We show that this is coupled with a significant reduction in endothelial cell proliferation in bbh mutants or integrin αvβ8 morphants. These data suggest that a complex involving βPix, GIT1 and integrin αvβ8 may regulate vascular stability, cerebral angiogenesis and endothelial cell proliferation in the developing embryo.