Current Drug Targets

Francis J. Castellino
Kleiderer-Pezold Professor of Biochemistry
Director, W.M. Keck Center for Transgene Research
Dean Emeritus, College of Science
230 Raclin-Carmichael Hall, University of Notre Dame
Notre Dame, IN 46556
USA

Back

Hypoxia Inducible Factor-1α, Endothelial Progenitor Cells, Monocytes,Cardiovascular Risk, Wound Healing, Cobalt and Hydralazine:A Unifying Hypothesis

Author(s): Michel R. Hoenig, Cesario Bianchi and Frank W. Sellke

Affiliation: Clinical Sciences Building, D Floor, D7 Office, Royal Brisbane&Women's Hospital, Herston Qld 4029,Australia.

Abstract:

Bone marrow-derived mononuclear cells differentiate into endothelial cells in adult animals, including humans. These cells, endothelial progenitor cells (EPCs), play central roles in neovascularization in a variety of physiological and pathological processes. EPCs numbers are clinically relevant; in patients with vascular disease, EPC numbers are predictive of hard clinical endpoints and correlate with vascular health in patients without manifest atherosclerosis. EPCs express CXCR4 which allows homing to sites of neovascularization. The homing signal released by the target tissues is SDF-1 which is the ligand for CXCR4. With release of SDF-1 and reversal of the marrow/periphery gradient, EPCs are mobilized to the periphery where they are recruited to SDF-1 expressing tissues. The SDF-1/CXCR4 axis is the final common pathway for EPC mobilization by hypoxia, angiogenic peptides and G-CSF. Expression of SDF-1 in target tissues and CXCR4 in EPCs as well as angiogenic cytokines such as VEGF are regulated by hypoxia inducible factor-1α (HIF-1α). This paper discusses evidence suggesting that depressed HIF-1α-mediated gene programming is the most fundamental of all cardiovascular risk factors and discusses the manipulation of this system with existing drugs such as Cobalt or Hydralazine. By stabilizing HIF-1α protein, these compounds will enhance EPC mobilization and function, thereby improving cardiovascular health overall. This paper discusses why previous studies with EPC transplantation or mobilization with G-CSF have had negative results and proposes the use of Cobalt and Hydralazine to enhance EPC function to overcome the dysfunctional EPC phenotype that is seen in patients with vascular disease or cardiovascular risk factors.

Keywords: Endothelial progenitor cell, angiogenesis, neovascularization, macrophage, hypoxia inducible factor, cobalt, hydralazine, stromal cell derived factor-1

Order Reprints Order Eprints Rights & PermissionsPrintExport

Article Details

VOLUME: 9
ISSUE: 5
Page: [422 - 435]
Pages: 14
DOI: 10.2174/138945008784221215
Price: $58