skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: VEGF-A, cytoskeletal dynamics, and the pathological vascular phenotype

Abstract

Normal angiogenesis is a complex process involving the organization of proliferating and migrating endothelial cells (ECs) into a well-ordered and highly functional vascular network. In contrast, pathological angiogenesis, which is a conspicuous feature of tumor growth, ischemic diseases, and chronic inflammation, is characterized by vessels with aberrant angioarchitecture and compromised barrier function. Herein we review the subject of pathological angiogenesis, particularly that driven by vascular endothelial growth factor (VEGF-A), from a new perspective. We propose that the serious structural and functional anomalies associated with VEGF-A-elicited neovessels, reflect, at least in part, imbalances in the internal molecular cues that govern the ordered assembly of ECs into three dimensional vascular networks and preserve vessel barrier function. Adopting such a viewpoint widens the focus from solely on specific pro-angiogenic stimuli such as VEGF-A to include a key set of cytoskeletal regulatory molecules, the Rho GTPases, which are known to direct multiple aspects of vascular morphogenesis including EC motility, alignment, multi-cellular organization, as well as intercellular junction integrity. We offer this perspective to draw attention to the importance of endothelial cytoskeletal dynamics for proper neovascularization and to suggest new therapeutic strategies with the potential to improve the pathological vascular phenotype.

Authors:
 [1];  [2]
  1. Department of Pathology, Beth Israel Deaconess Medical Center, Research North Building, 99 Brookline Avenue, Boston, MA 02215 (United States). E-mail: jnagy@bidmc.harvard.edu
  2. Department of Pathology, Beth Israel Deaconess Medical Center, Research North Building, 99 Brookline Avenue, Boston, MA 02215 (United States). E-mail: dsenger@bidmc.harvard.edu
Publication Date:
OSTI Identifier:
20775341
Resource Type:
Journal Article
Resource Relation:
Journal Name: Experimental Cell Research; Journal Volume: 312; Journal Issue: 5; Other Information: DOI: 10.1016/j.yexcr.2005.10.017; PII: S0014-4827(05)00484-2; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACTIN; GROWTH FACTORS; INFLAMMATION; MORPHOGENESIS; NEOPLASMS; PHENOTYPE

Citation Formats

Nagy, Janice A., and Senger, Donald R. VEGF-A, cytoskeletal dynamics, and the pathological vascular phenotype. United States: N. p., 2006. Web. doi:10.1016/j.yexcr.2005.10.017.
Nagy, Janice A., & Senger, Donald R. VEGF-A, cytoskeletal dynamics, and the pathological vascular phenotype. United States. doi:10.1016/j.yexcr.2005.10.017.
Nagy, Janice A., and Senger, Donald R. Fri . "VEGF-A, cytoskeletal dynamics, and the pathological vascular phenotype". United States. doi:10.1016/j.yexcr.2005.10.017.
@article{osti_20775341,
title = {VEGF-A, cytoskeletal dynamics, and the pathological vascular phenotype},
author = {Nagy, Janice A. and Senger, Donald R.},
abstractNote = {Normal angiogenesis is a complex process involving the organization of proliferating and migrating endothelial cells (ECs) into a well-ordered and highly functional vascular network. In contrast, pathological angiogenesis, which is a conspicuous feature of tumor growth, ischemic diseases, and chronic inflammation, is characterized by vessels with aberrant angioarchitecture and compromised barrier function. Herein we review the subject of pathological angiogenesis, particularly that driven by vascular endothelial growth factor (VEGF-A), from a new perspective. We propose that the serious structural and functional anomalies associated with VEGF-A-elicited neovessels, reflect, at least in part, imbalances in the internal molecular cues that govern the ordered assembly of ECs into three dimensional vascular networks and preserve vessel barrier function. Adopting such a viewpoint widens the focus from solely on specific pro-angiogenic stimuli such as VEGF-A to include a key set of cytoskeletal regulatory molecules, the Rho GTPases, which are known to direct multiple aspects of vascular morphogenesis including EC motility, alignment, multi-cellular organization, as well as intercellular junction integrity. We offer this perspective to draw attention to the importance of endothelial cytoskeletal dynamics for proper neovascularization and to suggest new therapeutic strategies with the potential to improve the pathological vascular phenotype.},
doi = {10.1016/j.yexcr.2005.10.017},
journal = {Experimental Cell Research},
number = 5,
volume = 312,
place = {United States},
year = {Fri Mar 10 00:00:00 EST 2006},
month = {Fri Mar 10 00:00:00 EST 2006}
}
  • In vitro research on vascular tissue engineering has extensively used isolated primary human or animal smooth muscle cells (SMC). Research programs that lack such facilities tend towards commercially available primary cells sources. Here, we aim to evaluate the capacity of commercially available human SMC to maintain their contractile phenotype, and determine if dedifferentiation towards the synthetic phenotype occurs in response to conventional cell culture and passaging without any external biochemical or mechanical stimuli. Lower passage SMC adopted a contractile phenotype marked by a relatively slower proliferation rate, higher expression of proteins of the contractile apparatus and smoothelin, elongated morphology, andmore » reduced deposition of collagen types I and III. As the passage number increased, migratory capacity was enhanced, average cell speed, total distance and net distance travelled increased up to passage 8. Through the various assays, corroborative evidence pinpoints SMC at passage 7 as the transition point between the contractile and synthetic phenotypes, while passage 8 distinctly and consistently exhibited characteristics of synthetic phenotype. This knowledge is particularly useful in selecting SMC of appropriate passage number for the target vascular tissue engineering application, for example, a homeostatic vascular graft for blood vessel replacement versus recreating atherosclerotic blood vessel model in vitro. - Highlights: • Ability of human smooth muscle cells to alter phenotype in culture is evaluated. • Examined the effect of passaging human smooth muscle cells on phenotype. • Phenotype is assessed based on morphology, proliferation, markers, and migration. • Multi-resolution assessment methodology, single-cell and cell-population. • Lower and higher passages than P7 adopted a contractile and synthetic phenotype respectively.« less
  • This article reports on the localization of two growth factor genes: vascular endothelial growth factor (VEGF) to human chromosome 6p12-p21 and placenta growth factor (PlGF) to human chromosome 14q24-q31. Such genetic mapping may aid in the identification of genes and mutations responsible for hereditary disorders. 8 refs., 1 fig.
  • Neuropilin-1 (Nrp1) is an essential receptor for angiogenesis that binds to VEGF-A. Nrp1 binds directly to VEGF-A with high affinity, but the nature of their selective binding has remained unclear. Nrp1 was initially reported to bind to the exon 7-encoded region of VEGF-A and function as an isoform-specific receptor for VEGF-A164/165. Recent data have implicated exon 8-encoded residues, which are found in all proangiogenic VEGF-A isoforms, in Nrp binding. We have determined the crystal structure of the exon 7/8-encoded VEGF-A heparin binding domain in complex with the Nrp1-b1 domain. This structure clearly demonstrates that residues from both exons 7 andmore » 8 physically contribute to Nrp1 binding. Using an in vitro binding assay, we have determined the relative contributions of exon 7- and 8-encoded residues. We demonstrate that the exon 8-encoded C-terminal arginine is essential for the interaction of VEGF-A with Nrp1 and mediates high affinity Nrp binding. Exon 7-encoded electronegative residues make additional interactions with the L1 loop of Nrp1. Although otherwise conserved, the primary sequences of Nrp1 and Nrp2 differ significantly in this region. We further show that VEGF-A{sub 164} binds 50-fold more strongly to Nrp1 than Nrp2. Direct repulsion between the electronegative exon 7-encoded residues of the heparin binding domain and the electronegative L1 loop found only in Nrp2 is found to significantly contribute to the observed selectivity. The results reveal the basis for the potent and selective binding of VEGF-A{sub 164} to Nrp1.« less
  • Coronary artery disease (CAD) and peripheral arterial disease (PAD) are significant medical problems worldwide. Although substantial progress has been made in prevention as well as in the treatment, particularly of CAD, there are a large number of patients, who despite maximal medical treatment have substantial symptomatology and who are not candidates for mechanical revascularization. Therapeutic angiogenesis represents a novel, conceptually appealing treatment option. Ad{sub GV}VEGF121.10 (BIOBYPASS) is an adenovector, carrying the transgene encoding for human vascular endothelial growth factor 121 (VEGF{sub 121}). A number of preclinical studies have demonstrated angiogenic activity of BIOBYPASS, not only anatomically but also functionally. Phasemore » I clinical studies have demonstrated that intramyocardial infection of BIOBYPASS in patients with severe CAD as well as intramuscular injections of BIOBYPASS in patients with severe peripheral vascular disease (PVD) was well tolerated; furthermore, these studies provided some intriguing indications of activity, which led to initiation of major randomized Phase II 'proof-of-concept' studies. This paper provides a review of the rationale behind BIOBYPASS as well as a summary of pertinent preclinical and early clinical data.« less