In:
Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 107, No. 5 ( 2010-09-03), p. 592-601
Kurzfassung:
The ICAP1 (integrin cytoplasmic domain–associated protein-1) is a specific intracellular binding protein of β1-integrins and the cerebral cavernous malformation (CCM) protein CCM1. ICAP1 recruits CCM1 to the cell membrane and activates CCM1 by changing its conformation. Because CCM1 plays a critical role for cardiovascular development, we hypothesized that its activator ICAP1 is involved in vascular differentiation. Objective: The objective of this study was to define the role of ICAP1 in endothelial cells. Methods and Results: Loss of ICAP1 in primary human endothelial cells causes excessive angiogenic branching and network formation in vitro (3D sprouting angiogenesis) and in vivo (xenotransplantation of ICAP1-silenced human endothelial cells). ICAP1 increases cell motility and the initial formation of capillary sprouts but prevents vessel outgrowth. ICAP1 inhibits Rho kinase activity and ERK (extracellular signal-regulated kinase) phosphorylation and induces expression of the cell cycle inhibitors p21 and p27 , leading to less endothelial proliferation. However, ICAP1 promotes endothelial survival and AKT phosphorylation. Global gene expression analyses revealed that the ICAP1 effects are mediated by strong activation of DELTA-NOTCH signaling. Active NOTCH1 or silencing of the NOTCH ligand DLL4 phenocopy the ICAP1 effects and blockade of NOTCH cleavage rescues the ICAP1-mediated defects in endothelial cells. Both ICAP1 and NOTCH1 reduce the expression of ESM1 (endothelial cell–specific molecule-1), and silencing of ESM1 disturbs vascular endothelial growth factor– or fibroblast growth factor 2–induced sprouting angiogenesis. Conclusions: In this study, we identified ICAP1 as a novel regulator to prevent excessive sprouting angiogenesis.
Materialart:
Online-Ressource
ISSN:
0009-7330
,
1524-4571
DOI:
10.1161/CIRCRESAHA.110.217257
Sprache:
Englisch
Verlag:
Ovid Technologies (Wolters Kluwer Health)
Publikationsdatum:
2010
ZDB Id:
1467838-X
