Substance P-Mediated Vascular Protection Ameliorates Bone Loss

Estrogen deficiency causes bone loss via diverse pathological cellular events. The involvement of the vasculature in bone formation has been widely studied, and type H vasculature has been found to be closely related to bone healing. Ovariectomy- (OVX-) induced estrogen deficiency reduces type H vessel density and promotes reduction of bone density. Analysis of early events after OVX showed that estrogen deficiency preferentially induces oxidative stress, which might provoke endothelial dysfunction and reduce angiogenic factors systemically and locally. The instability of the vascular potential is expected to promote bone loss under estrogen deficiency. Substance P (SP) is an endogenous neuropeptide that controls inflammation and prevents cell death under pathological conditions. SP can elevate nitric oxide production in endothelial cells and inhibit endothelial dysfunction. This study is aimed at investigating the preventive effects of systemically injected SP on OVX-induced vascular loss and osteoporosis onset. SP was systemically administered to OVX rats twice a week for 4 weeks, immediately after OVX induction. OVX conditions could decrease antioxidant enzyme activity, type H vessels, and angiogenic growth factors in the bone marrow, followed by inflammation and bone loss. However, pretreatment with SP could block type H vessel loss, accompanied by the enrichment of nitric oxide and sustained angiogenic factors. SP-mediated early vascular protection inhibits bone density reduction. Altogether, this study suggests that early administration of SP can block osteoporosis development by modulating oxidative stress and protecting the bone vasculature and angiogenic paracrine potential at the initial stage of estrogen deficiency.