Angiogenesis plays an important role in a variety of pathological conditions, including tumor growth and metastasis, rheumatoid arthritis and diabetic retinopathy. In addition to their mitogenic activity, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) also protect endothelial cells (EC) from apoptosis, an event thought to facilitate survival and integration of invasive EC into neovessels. We have shown that VEGF and bFGF preferentially protect ECs from extrinsic (death-receptor) and intrinsic (stress) pathways of apoptosis, respectively. Furthermore, the serine/threonine kinase Raf-1, which promotes EC survival, is differentially activated by each growth factor. Specifically, Src phosphorylates YY340/1 downstream of VEGF, while p21-activated kinase (PAK) phosphorylates SS338/9 downstream of bFGF. Interestingly, only after bFGF stimulation is Raf-1 translocated to the mitochondria. We hypothesize that differential phosphorylation and cellular localization of Raf-1 by VEGF vs. bFGF is responsible for protection against distinct pathways of apoptosis. We will dissect the molecular basis of these responses using Raf-1 mutants to determine the role of the Src and PAK activation sites in EC survival and angiogenesis. The results of these studies will shed light on compensatory mechanisms underlying the cytoprotective effect of distinct growth factors and will enhance strategies to target EC survival pathways in anti-angiogenic therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32HL073609-01
Application #
6649133
Study Section
Special Emphasis Panel (ZRG1-F10 (20))
Program Officer
Schucker, Beth
Project Start
2003-05-01
Project End
2005-04-30
Budget Start
2003-05-01
Budget End
2004-04-30
Support Year
1
Fiscal Year
2003
Total Cost
$41,608
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037