Cardiovascular disease is the number 1 cause of death in the United States. Incomplete vascular repair resulting from inappropriate growth of vascular smooth muscle cells (SMC) coupled with deficient reendothelialization is a major limitation of interventional therapies. Approaches are being developed that aim to either inhibit SMC hyperplasia or stimulate reendothelialization. However, it has become clear that regulation of these two processes is difficult to achieve independently. A principal reason for this likely lies in the relationship between 2 of the key growth factors involved in these processes, basic fibroblast growth factor (FGF2) and vascular endothelial growth factor (VEGF). While excessive FGF2 activity is thought to contribute to SMC hyperplasia, insufficient VEGF activity is believed to underlie deficient reendothelialization. Our results have revealed significant similarities in the manner by which heparan sulfate proteoglycans (HSPG) modulate these 2 growth factors, yet we have also identified distinctions. These finding have led us to hypothesize that HSPG structure and distribution dictate the vascular cell response to FGF2 and VEGF. Thus, it is the goal of the present proposal to identify the specific elements underlying HSPG modulation of FGF2 and VEGF within vascular cells (smooth muscle and endothelial), such that this information can eventually be exploited to effectively stimulate vascular repair without restenosis.
The specific aims of this proposal are: 1. Identify the pH sensitive heparin-binding domain within VEGF121/165 and characterize its function. 2. Define the role of HSPG and lipid rafts in endothelial and smooth muscle cells on VEGF121/165 and FGF2 binding, trafficking, and activity. 3. Determine the specific heparan sulfate structures required for VEGF and FGF2 binding within endothelial HSPG. 4. Evaluate the role of syndecan 4 and lipid rafts in the vascular response to VEGF and FGF2 in vivo. We plan to utilize a multidisciplinary approach involving a combination of molecular, biochemical, biophysical, and theoretical methods along with animal studies to expose the complexities of HSPG modulation of FGF2 and VEGF. These studies will have wide ranging impact on vascular biology and will likely reveal previously undefined mechanisms of growth factor control that could help identify targets for clinical modulation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL056200-09A1
Application #
6985065
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Ershow, Abby
Project Start
1997-01-01
Project End
2009-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
9
Fiscal Year
2005
Total Cost
$363,205
Indirect Cost
Name
Boston University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Vora, Siddharth R; Palamakumbura, Amitha H; Mitsi, Maria et al. (2010) Lysyl oxidase propeptide inhibits FGF-2-induced signaling and proliferation of osteoblasts. J Biol Chem 285:7384-93
Symes, Karen; Smith, Erin M; Mitsi, Maria et al. (2010) Sweet cues: How heparan sulfate modification of fibronectin enables growth factor guided migration of embryonic cells. Cell Adh Migr 4:507-10
Spencer, Jean L; Bernanke, Joel A; Buczek-Thomas, Jo Ann et al. (2010) A computational approach for deciphering the organization of glycosaminoglycans. PLoS One 5:e9389
Kurtagic, Elma; Jedrychowski, Mark P; Nugent, Matthew A (2009) Neutrophil elastase cleaves VEGF to generate a VEGF fragment with altered activity. Am J Physiol Lung Cell Mol Physiol 296:L534-46
Smith, Erin M; Mitsi, Maria; Nugent, Matthew A et al. (2009) PDGF-A interactions with fibronectin reveal a critical role for heparan sulfate in directed cell migration during Xenopus gastrulation. Proc Natl Acad Sci U S A 106:21683-8
Mitsi, Maria; Forsten-Williams, Kimberly; Gopalakrishnan, Manoj et al. (2008) A catalytic role of heparin within the extracellular matrix. J Biol Chem 283:34796-807
Forsten-Williams, Kimberly; Chu, Chia Lin; Fannon, Michael et al. (2008) Control of growth factor networks by heparan sulfate proteoglycans. Ann Biomed Eng 36:2134-48
Fannon, Michael; Forsten-Williams, Kimberly; Nugent, Matthew A et al. (2008) Sucrose octasulfate regulates fibroblast growth factor-2 binding, transport, and activity: potential for regulation of tumor growth. J Cell Physiol 215:434-41
Buczek-Thomas, Jo Ann; Hsia, Edward; Rich, Celeste B et al. (2008) Inhibition of histone acetyltransferase by glycosaminoglycans. J Cell Biochem 105:108-20
Ghosh, Shivam; Gopalakrishnan, Manoj; Forsten-Williams, Kimberly (2007) Self-consistent theory of reversible ligand binding to a spherical cell. Phys Biol 4:344-54

Showing the most recent 10 out of 29 publications