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 an acidic, hypoxic wound environment. We have previously shown that osteoblasts 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, and determined their relative contribution to regulation of rat calvarial osteoblast VEGF production under both normoxic and hypoxic conditions. Our results 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 transcriptionally regulated, because the rate of VEGF mRNA degradation was unchanged at pH 7.0 vs. 7.4. Similarly, an elevated lactate concentration (22 mM) also depressed osteoblast elaboration of VEGF at both neutral and acidic pH (P < 0.001). Furthermore, the effects of increasing acidity and elevated lactate appeared to be additive.
Spector
J A
JA
Laboratory of Developmental Biology and Repair, Department of Surgery, New York University School of Medicine, New York, New York 10016, USA.
Mehrara
B J
BJ
Greenwald
J A
JA
Saadeh
P B
PB
Steinbrech
D S
DS
Bouletreau
P J
PJ
Smith
L P
LP
Longaker
M T
MT
D000140:Acidosis, Lactic / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism*; D050723:Fractures, Bone / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006207:Half-Life; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D019344:Lactic Acid / Q000378:metabolism / Q000494:pharmacology; D008222:Lymphokines / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014945:Wound Healing / Q000502:physiology*
D016228:Endothelial Growth Factors; D008222:Lymphokines; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019344:Lactic Acid