CIB1 regulates endothelial cells and ischemia-induced pathological and adaptive angiogenesis.
Pathological angiogenesis contributes to various ocular, malignant, and inflammatory disorders, emphasizing the need to understand this process on a molecular level. CIB1 (calcium- and integrin-binding protein), a 22-kDa EF-hand-containing protein, modulates the activity of p21-activated kinase 1 in fibroblasts. Because p21-activated kinase 1 also contributes to endothelial cell function, we hypothesized that CIB1 may have a role in angiogenesis. We found that endothelial cells depleted of CIB1 by either short hairpin RNA or homologous recombination have reduced migration, proliferation, and tubule formation. Moreover, loss of CIB1 in these cells decreases p21-activated kinase 1 activation, downstream extracellular signal-regulated kinase 1/2 activation, and matrix metalloproteinase 2 expression, all of which are known to contribute to angiogenesis. Consistent with these findings, tissues derived from CIB1-deficient (CIB1-/-) mice have reduced growth factor-induced microvessel sprouting in ex vivo organ cultures and in vivo Matrigel plugs. Furthermore, in response to ischemia, CIB1-/- mice demonstrate decreased pathological retinal and adaptive hindlimb angiogenesis. Ischemic CIB1-/- hindlimbs also demonstrate increased tissue damage and significantly reduced p21-activated kinase 1 activation. These data therefore reveal a critical role for CIB1 in ischemia-induced pathological and adaptive angiogenesis.
Zayed
Mohamed A
MA
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Yuan
Weiping
W
Leisner
Tina M
TM
Chalothorn
Dan
D
McFadden
Andrew W
AW
Schaller
Michael D
MD
Hartnett
M Elizabeth
ME
Faber
James E
JE
Parise
Leslie V
LV
D042501:Angiogenic Proteins / Q000032:analysis; D000818:Animals; D002135:Calcium-Binding Proteins / Q000172:deficiency / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology* / Q000502:physiology; D006614:Hindlimb / Q000098:blood supply / Q000473:pathology; D007511:Ischemia / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D054462:p21-Activated Kinases / Q000378:metabolism
D042501:Angiogenic Proteins; D002135:Calcium-Binding Proteins; C491605:Cib1 protein, mouse; D054462:p21-Activated Kinases