Expression of RAC2 in endothelial cells is required for the  postnatal neovascular response.
Herein, we describe an obligate role for the hematopoietic specific GTPase, RAC2 in endothelial integrin signaling and the postnatal neovascularization response in vivo. Using a Rac2 knockout mouse model, we discovered that despite the presence of both RAC1 and RAC2 protein in endothelial cells, RAC2 is obligately required for the postnatal neovascular response and alphavbeta3/ alpha4beta1/alpha5beta1 integrin-directed migration on vitronectin, H296 and CH271, fibronectin fragments, respectively. The molecular basis for RAC2 specificity was explored. A genetic analysis of Syk -/+ or Syk-/+;Rac2 -/+ mice revealed that SYK kinase is required for the integrin induced activation of RAC2. The analysis of endothelial cells from Rac2-/+ versus Syk-/+;Rac2-/+ mice provided genetic evidence that SYK-RAC2 signaling axis regulates integrin (alphavbeta3, alpha4beta1 and alpha5beta1) dependent migration. Our results provide evidence that a specific region of the nonreceptor protein tyrosine kinase, SYK, the B linker region containing Y342 and Y346 is required for SYK's regulation of RAC2 and integrin dependent migration. Moreover, the capacity of mice to vascularize the ischemic hindlimb following femoral artery ligation or matrigel plugs was markedly reduced in mice homozygous deficient for the Rac2 gene. These findings identify a novel signaling axis for the induction and potential modulation of postnatal angiogenesis.
De
Pradip
P
Department of Pediatrics, Aflac Cancer Center and Blood Disorders Service, Emory University School of Medicine, Atlanta, GA 30322, USA.
Peng
Qiong
Q
Traktuev
Dmitry O
DO
Traktuevc
Dmitry O
DO
Li
Weiming
W
Yoder
Mervin C
MC
March
Keith L
KL
Durden
Donald L
DL
D000818:Animals; D019556:COS Cells; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002522:Chlorocebus aethiops; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005353:Fibronectins / Q000494:pharmacology; D015870:Gene Expression; D006614:Hindlimb / Q000503:physiopathology; D006801:Humans; D039041:Integrin alpha4beta1 / Q000502:physiology; D039302:Integrin alphaVbeta3 / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D010215:Papio; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D012039:Regional Blood Flow / Q000502:physiology; D015427:Reperfusion Injury / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology; D000072377:Syk Kinase; D019096:Vitronectin / Q000494:pharmacology; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein
D005353:Fibronectins; D039041:Integrin alpha4beta1; D039302:Integrin alphaVbeta3; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D011505:Protein-Tyrosine Kinases; D034741:RNA, Small Interfering; D000072377:Syk Kinase; D019096:Vitronectin; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein; C484602:Rac1 protein, mouse; C000606896:SYK protein, human; C000606897:Syk protein, mouse