Osteoblast expression of vascular endothelial growth factor is modulated by the extracellular microenvironment

Angiogenesis, the formation of new blood vessels, is crucial to the process of fracture healing. Vascular disruption after osseous injury results in a n acidic, hypoxic wound environment. We have previously shown that osteobla sts can produce vascular endothelial growth factor (VEGF) in response to a variety of stimuli. In this study we examined pH and lactate concentration, two components of the putative fracture extracellular microenvironment, an d determined their relative contribution to regulation of rat calvarial ost eoblast VEGF production under both normoxic and hypoxic conditions. Our res ults demonstrate that pH and lactate concentration do independently affect osteoblast VEGF mRNA and protein production. Acidic pH (7.0) significantly decreased VEGF production, under normoxic and hypoxic conditions (P< 0.05), compared with neutral pH (7.4). This decrease was primarily transcriptiona lly regulated, because the rate of VEGF mRNA degradation was unchanged at p H 7.0 vs. 7.4. Similarly, an elevated lactate concentration (22 mM) also de pressed osteoblast elaboration of VEGF at both neutral and acidic pH (P< 0. 001). Furthermore, the effects of increasing acidity and elevated lactate a ppeared to be additive.