Relaxin induces vascular endothelial growth factor expression and angiogenesis selectively at wound sites.
Relaxin is a reproductive hormone that has historically been characterized as being responsible for pubic ligament loosening and cervical ripening. Recently, relaxin has been associated with neovascularization of the endometrial lining of the uterus, potentially via specific induction of vascular endothelial growth factor. Previously conducted clinical studies using partially purified porcine relaxin have described relaxin's ability to stimulate the healing of ischemic wounds, suggesting that relaxin may also have angiogenic effects at sites of ischemic wound healing. In the present study, relaxin's angiogenic effects in the context of wound repair were tested in rodent models of angiogenesis and wound healing. Relaxin showed an ability to stimulate new blood vessel formation, particularly at ischemic wound sites, and to induce both vascular endothelial growth factor and basic fibroblast growth factor specifically in cells, presumably including macrophages, collected from wound sites. Resident macrophages collected from nonwound sites, such as the lung, did not show altered expression of these cytokines following relaxin administration. Because angiogenic wound cells are frequently macrophages, THP-1 cells, a cell line of monocyte lineage that binds relaxin specifically, were tested for and shown to induce vascular endothelial growth factor and basic fibroblast growth factor in response to relaxin. In conclusion, relaxin may be useful in the treatment of ischemic wounds by stimulating angiogenesis via the induction of vascular endothelial growth factor and basic fibroblast growth factor in wound macrophages.
Unemori
E N
EN
Connetics Corporation, Palo Alto, CA, USA.
Lewis
M
M
Constant
J
J
Arnold
G
G
Grove
B H
BH
Normand
J
J
Deshpande
U
U
Salles
A
A
Pickford
L B
LB
Erikson
M E
ME
Hunt
T K
TK
Huang
X
X
D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D007511:Ischemia / Q000150:complications / Q000188:drug therapy*; D008222:Lymphokines / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D012065:Relaxin / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014945:Wound Healing / Q000187:drug effects*; D014947:Wounds and Injuries / Q000150:complications / Q000188:drug therapy*
D016207:Cytokines; D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D012065:Relaxin