Article

Selective Requirement for Src Kinases during VEGF-Induced Angiogenesis and Vascular Permeability

Department of Immunology, Scripps Research Institute, La Jolla, California 92037, USA.
Molecular Cell (Impact Factor: 14.46). 01/2000; 4(6):915-24. DOI: 10.1016/S1097-2765(00)80221-X
Source: PubMed

ABSTRACT Src kinase activity was found to protect endothelial cells from apoptosis during vascular endothelial growth factor (VEGF)-, but not basic fibroblast growth factor (bFGF)-, mediated angiogenesis in chick embryos and mice. In fact, retroviral targeting of kinase-deleted Src to tumor-associated blood vessels suppressed angiogenesis and the growth of a VEGF-producing tumor. Although mice lacking individual Src family kinases (SFKs) showed normal angiogenesis, mice deficient in pp60c-src or pp62c-yes showed no VEGF-induced vascular permeability (VP), yet fyn-/- mice displayed normal VP. In contrast, inflammation-mediated VP appeared normal in Src-deficient mice. Therefore, VEGF-, but not bFGF-, mediated angiogenesis requires SFK activity in general, whereas the VP activity of VEGF specifically depends on the SFKs, Src, or Yes.

Download full-text

Full-text

Available from: Brian P Eliceiri, Jul 02, 2015
0 Followers
 · 
160 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The spinal cord has the ability to regenerate but the microenvironment generated after trauma reduces that capacity. An increase in Src family kinase (SFK) activity has been implicated in neuropathological conditions associated with central nervous system trauma. Therefore, we hypothesized that a decrease in SFK activation by a long-term treatment with 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyramidine (PP2), a selective SFK inhibitor, after spinal cord contusion with the New York University (NYU) impactor device would generate a permissive environment that improves axonal sprouting and/or behavioral activity. Results demonstrated that long-term blockade of SFK activation with PP2 increases locomotor activity at 7, 14, 21 and 28 days post-injury in the Basso, Beattie, and Bresnahan open field test, round and square beam crossing tests. In addition, an increase in white matter spared tissue and serotonin fiber density was observed in animals treated with PP2. However, blockade of SFK activity did not change the astrocytic response or infiltration of cells from the immune system at 28 days post-injury. Moreover, a reduced SFK activity with PP2 diminished Ephexin (a guanine nucleotide exchange factor) phosphorylation in the acute phase (4 days post-injury) after trauma. Together, these findings suggest a potential role of SFK in the regulation of spared tissue and/or axonal outgrowth that may result in functional locomotor recovery during the pathophysiology generated after spinal cord injury. Our study also points out that ephexin1 phosphorylation (activation) by SFK action may be involved in the repulsive microenvironment generated after spinal cord injury.
    Neural Regeneration Research 12/2014; 9(24):2164-73. DOI:10.4103/1673-5374.147949
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Transient disruption of endothelial adherens junctions and cytoskeletal remodeling are responsible for increases in vascular permeability induced by inflammatory stimuli and vascular endothelial growth factor (VEGF). Nitric oxide (NO) produced by endothelial NO synthase (eNOS) is critical for VEGF induced changes in permeability in vivo, however, the molecular mechanisms by which endogenous NO modulates endothelial permeability is not clear. Here we show that the lack of eNOS reduces VEGF induced permeability, an effect mediated by enhanced Rac-GTPase activation and stabilization of cortical actin. The loss of NO, increased the recruitment of the Rac-GEF, Tiam-1, to adherens junctions and VE-cadherin and reduced Rho-activation and stress fiber formation. In addition, NO deficiency reduced VEGF-induced VE-cadherin phosphorylation, and impaired the localization, but not the activation, of c-src to cell junctions. The physiological role of eNOS activation is clear since VEGF, histamine and inflammation induced vascular permeability is reduced in mice with bearing the knockin mutation of the key phosphorylation site S1176. Thus, NO is critical for Rho GTPase dependent regulation of cytoskeletal architecture leading to reversible changes in vascular permeability.
    Journal of Cell Science 05/2014; 127(Pt 9):2120. DOI:10.1242/jcs.153601
  • Source
    Canadian Journal of Diabetes 10/2013; 37S4:S2. DOI:10.1016/j.jcjd.2013.08.004