Acute Menopause Inhibits Angiogenesis More Than Age-Related Menopause

INTRODUCTION: Cardiovascular events increase with premature menopause. Similarly, peripheral arterial disease rates increase postmenopause. In murine hindlimb ischemia models, increasing age and female sex correlate with decreased blood flow recovery and angiogenesis. The impact of premature vs natural menopause on neovascularization is unknown. Hypothesis: angiogenesis and blood flow recovery will be superior in young female mice compared to oophorectomized (OVX) mice, middle-aged or old mice. METHODS: Young female C57BL/6 mice (14-16 weeks) were compared to OVX young mice (premature menopause), postmenopausal middle-aged (58-62 weeks) and old (104-108 weeks) female mice. All underwent femoral artery transection and ligation (n = 7-9 per group). Laser Doppler data was collected at three time points (preoperative, immediately post ligation, and postoperative day 14). Immunohistochemistry was performed using anti-CD31 antibodies on the gastrocnemius muscle. Capillary density was determined by #vessels/5HPF. ANOVA was performed, p < 0.05 considered significant. RESULTS: Blood flow recovery in OVX mice was similar to middle-aged and old mice, but was lower compared to young non-OVX mice (0.63 ± 0.04 vs 0.42 ± 0.02). Angiogenesis was decreased in OVX young females compared to young (50.8%), middle-aged (56.4%) and old (21.7%) non-OVX mice. Old mice had decreased angiogenesis compared to young (37.3%) non-OVX and middle-aged mice (44.3%). CONCLUSION: Our results suggest premature menopause is more detrimental than natural menopause to angiogenesis following ischemic injury. Implied is the importance of hormonal interaction with response to vascular injury. Further understanding of menopause in vascular remodeling may allow for targeted preventative therapies in critical limb ischemia.