Regular Article
Fibroblast Response to Hypoxia: The Relationship between Angiogenesis and Matrix Regulation

Presented at the Annual Meeting of the Association for Academic Surgery, Seattle, Washington, November 18–22, 1998
https://doi.org/10.1006/jsre.1999.5627Get rights and content
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Abstract

A number of studies have demonstrated the critical role of angiogenesis for successful wound repair in the surgical patient. Vascular disruption from tissue injury due to trauma or surgery leads to a hypoxic zone in the healing wound. In this dynamic process, angiogenesis is vital for the delivery of oxygen, nutrients, and growth factors necessary to initiate the synthetic processes of wound healing. Fibroblasts, invading the wound early in the healing process, are involved in extracellular matrix (ECM) deposition as well as wound contraction. However, the exact mechanisms by which important genes are regulated remain unknown. In order to examine these processes, we studied the effects of hypoxia on fibroblasts for the expression of VEGF, type IαI collagen, and matrix-metalloproteinase-3, three genes essential for the regulation of angiogenesis, ECM deposition, and ECM degradation in wound healing.

Primary cell cultures of normal human dermal fibroblasts (NHDFs) were placed in hypoxia for varying periods of time. Northern blot hybridization was performed with [α32P]dCTP-labeled cDNA probes for VEGF, type IαI collagen, and MMP-3.

The results demonstrated a time-dependent VEGF mRNA upregulation (470% of baseline) under hypoxia. Type IαI collagen increased (170% of baseline) at 24 h, but was then abruptly downregulated to 3.8% of baseline at 48 h. MMP-3 was incrementally downregulated to 2.2% of baseline at 48 h.

These experiments focused on the effect of hypoxia on genes thought to play a role in wound repair. VEGF upregulation in the hypoxic microenvironment of the early wound may serve to stimulate angiogenesis. Type IαI collagen, though upregulated early on, was abruptly downregulated at 48 h. This downregulation may reflect the in vivo requirement for angiogenesis to deliver oxygen for successful hydroxylation and collagen synthesis in the wound. MMP-3, also downregulated at 48 h, may also implicate the need for angiogenesis. These data support the theory that hypoxia-driven angiogenesis is critical for ECM formation and remodeling in successful soft tissue repair. Furthermore, they may represent the role of hypoxia as an important regulator to efficiently balance these complex processes in the healing wound.

Keywords

hypoxia
VEGF
MMP-3
collagen
fibroblast
angiogenesis
wound repair

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1

To whom correspondence should be addressed at Department of Surgery, New York University Medical Center, 530 First Avenue, Suite 10W, New York, NY 10016. Fax: (212) 263-0481.