Hyperoxia and angiogenesis

Abstract

We hypothesized that tissue hyperoxia would enhance and hypoxia inhibit neovascularization in a wound model. Therefore, we used female Swiss-Webster mice to examine the influence of differential oxygen treatment on angiogenesis. One milliliter plugs of Matrigel, a mixture of matrix proteins that supports but does not itself elicit angiogenesis, were injected subcutaneously into the mice. Matrigel was used without additive or with added vascular endothelial growth factor (VEGF) or anti-VEGF antibody. Animals were maintained in hypoxic, normoxic, or one of four hyperoxic environments: hypoxia -- 13 percent oxygen at 1 atmosphere absolute (ATA); normoxia -- 21 percent oxygen at 1 ATA; hyperoxia -- (groups a-d) 100 percent oxygen for 90 minutes twice daily at the following pressures: Group a, 1 ATA; Group b, 2 ATA; Group c, 2.5 ATA; Group d, 3.0 ATA. Subcutaneous oxygen tension was measured in all groups. The Matrigel was removed 7 days after implantation. Sections were graded microscopically for the extent of neovascularization. Angiogenesis was significantly greater in all hyperoxic groups and significantly less in the hypoxic group compared with room air-exposed controls. Anti-VEGF antibody abrogated the angiogenic effect of both VEGF and increased oxygen tension. We conclude that angiogenesis is proportional to ambient pO(2) over a wide range. This confirms the clinical impression that angiogenesis requires oxygen. Intermittent oxygen exposure can satisfy the need for oxygen in ischemic tissue.

Wound angiogenesis as a function of tissue oxygen tension: A mathematical model

“…First, the model suggests that an extremely hypoxic wound environment cannot sustain vascular growth (10)(11)(12)14). Second, hyperoxia promotes wound angiogenesis and healing (2,16,18,57). Furthermore, the model simulations indicate that there is an optimal level of hyperoxia beyond which the beneficial effects of hyperoxia may be reversed.…”

“…Although hypoxia is generally recognized as a physiological cue to induce angiogenesis (7-10), severe hypoxia cannot sustain the growth of functional blood vessels (2,(11)(12)(13)(14). Interestingly, like hypoxia, hyperoxia also induces the expression of angiogenic factors and supports wound angiogenesis and healing (2,(15)(16)(17).…”

“…Healing wounds make excellent experimental models that can provide otherwise unavailable insights into the nature of angiogenesis (2). However, a series of events must occur for a vascular network to form in the wound site.…”

“…Inflammatory cells, like neutrophils and macrophages, migrate into the wound to degrade necrotic tissue and bacteria. The coagulation proteins, inflammatory cells, and metabolic byproducts provide a flood of growth and angiogenic factors into the wound environment, which is conditioned to a moderate hypoxia, an accumulation of lactate, a slight lowering of pH, and an elevation of pCO 2 (3,4). These angiogenic factors recruit fibroblasts and endothelial cells, which accumulate in the wound region.…”

Correction of Hypoxia, a Critical Element for Wound Bed Preparation Guidelines: TIMEO2 Principle of Wound Bed Preparation

“…[20][21][22] The rate at which normal wounds heal has been shown to be oxygen dependent. Fibroblast replication, collagen deposition, 16 angiogenesis, [23][24][25][26] resistance to infection, [27][28][29] increases to . 40 mm Hg (increase might be delayed).…”