The Role of Vascular Endothelial Growth Factor in Wound Healing

Background

A chronic wound is tissue with an impaired ability to heal. This is often a consequence of one of the following etiologies: diabetes, venous reflux, arterial insufficiency sickle cell disease, steroids, and/or pressure. Healing requires granulation tissue depending on epithelialization and angiogenesis. Currently no growth factor is available to treat patients with impaired healing that stimulates both epithelialization and angiogenesis. The objective is to review is the multiple mechanisms of vascular endothelial growth factor (VEGF) in wound healing.

Materials and Methods

The authors reviewed the literature on the structure and function of VEGF, including its use for therapeutic angiogenesis. Particular attention is given to the specific role of VEGF in the angiogenesis cascade, its relationship to other growth factors and cells in a healing wound.

Results

VEGF is released by a variety of cells and stimulates multiple components of the angiogenic cascade. It is up-regulated during the early days of healing, when capillary growth is maximal. Studies have shown the efficacy of VEGF in peripheral and cardiac ischemic vascular disease with minimal adverse effects. Experimental data supports the hypothesis that VEGF stimulates epithelialization and collagen deposition in a wound.

Conclusion

VEGF stimulates wound healing through angiogenesis, but likely promotes collagen deposition and epithelialization as well. Further study of the molecule by utilizing the protein itself, or novel forms of delivery such as gene therapy, will increase its therapeutic possibilities to accelerate closure of a chronic wound.

Introduction

The term “chronic wound” describes a wound that occurs in a patient who has physiological impairments to healing (Table 1). These pathophysiologic processes predispose cutaneous wounds to deviate from the characteristics of acute wound healing. Although a chronic wound is not always slow to heal, it should be considered “emergent” in that it is often a nonhealing wound. An estimated 3 to 6 million chronic skin ulcers occur in patients every year in the United States. The most common underlying conditions are venous reflux, pressure, and diabetes mellitus [1, 2, 3, 4, 5].

In the vast majority of surgical procedures, nearly all acute wounds heal in an orderly and timely process [6], with a strength and integrity similar to normal skin [7, 8]. Wounds refractory to moist healing, however, may be candidates for growth factor therapy, which is assumed to stimulate missing or dysfunctional components of the chronic wound [9, 10, 11]. An angiogenic growth factor may promote closure of chronic wounds exhibiting hypoxia and compromised vascularity.

Vascular endothelial growth factor (VEGF) is one such candidate. It functions as an endothelial cell mitogen [12, 13, 14, 15, 16, 17], chemotactic agent [18, 19], and inducer of vascular permeability [20, 21, 22, 23, 24, 25, 26]. Other angiogenic growth factors such as basic fibroblast growth factor (bFGF) and transforming growth factor beta (TGF-β) have been described, but VEGF is unique for its effects on multiple components of the wound-healing cascade, including angiogenesis and recently shown epithelialization and collagen deposition [27]. Purified growth factors [28] and cultured human cells [29, 30, 31] have both been approved by the Food and Drug Administration to accelerate closure of nonhealing wounds. This has transformed the field of wound healing by establishing the efficacy of a topical growth factor and cell therapy. Since angiogenesis maintains a critical role in wound healing, in the future, VEGF (alone or in combination therapy) may be used on patients with nonhealing wounds. This article reviews the role of angiogenesis and other mechanisms of VEGF in wound healing.