Changes in vasoactive factors associated with altered vessel morphology in the tibial metaphysis during ovariectomy-induced bone loss in rats.

We hypothesized that estrogen deficiency induces changes in bone vascularization which might be involved in bone loss mechanisms. First, we studied gene expression of angiogenic (vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2)) and vasodilator (endothelial nitric oxide synthase (ecNOS), neuronal NOS (nNOS), inducible NOS (iNOS), PTH-related protein (PTHrP), and its receptor PTH/PTHrP) factors in proximal tibial metaphysis of ovariectomized (OVX) rats and OVX 17beta-estradiol-treated rats at 3, 7, and 14 days. We then evaluated bone and vessel histomorphometry in secondary spongiosae by infusing vessels with a mixture of India ink/barium sulfate after 7 and 14 days of OVX. After 7 days expression of angiogenic and vasodilator factors decreased, concomitant with a decrease in the bone vessel number and possibly area. After 14 days all factors except FGF-2 exhibited either increased or normalized expression, which was associated with the stimulation of both bone formation and resorption. 17beta-Estradiol administration for 7 or 14 days prevented not only the OVX-induced changes in bone remodeling but also the morphological alterations observed in bone vessels. It also prevented the alterations in the expression of genes modified by OVX, except for that of FGF-2 whose transcription was similarly down-regulated in OVX rats with or without estrogen treatment.