As part of the mini-symposium entitled "Divergent Impacts of Physical Activity and Sedentary Behavior on Glucose Intolerance and Vascular Function: From Laboratory to Clinic," this presentation shares data on the role of increased physical activity and sedentary behavior in mediating cardiovascular disease.

Postmenopausal women have an increased risk for heart disease. Ovariectomized mouse models show changes in body weight, adipose tissue, and systemic inflammation within 8-12 weeks following ovariectomy. These pathological changes may contribute to cardiac dysfunction after menopause. However, early changes in cardiac markers that may lead to dysfunction and disease remain unclear. Objective: To evaluate differences in cardiac gene expression between 8-week post-ovariectomy and control mice. Methods: Myocardial RNA was isolated from ovariectomized (OVX, n=10) and sham surgery (SHAM, n=10) adult mice 8 weeks following surgery. Fetal gene program, fibrosis, and angiotensin II gene expression were determined via RT-PCR. Differences between groups were analyzed using two sample t-tests. Results: Compared to SHAM, OVX mice exhibited a fetal gene expression pattern similar to that observed in failing hearts including increased B-type natriuretic peptide (p=0.02), atrial natriuretic peptide (p=0.06) and alpha skeletal actin (p=0.01) and decreased alpha and beta myosin heavy chain isoform expression (p=0.05, p=0.02, respectively). Expression of fibrotic genes vimentin (p=0.01), fibronectin (p=0.02), collagen1 (p=0.04), and collagen3 (p=0.03) were greater in OVX compared with SHAM. Lastly, angiotensin II was also significantly greater in OVX (p=0.001). Conclusion: Ovariectomized mice begin to exhibit maladaptive gene expression within 8 weeks after surgery, indicating that ovarian hormone loss initiates a pathological response in the heart at early time points that may be related to angiotensin II-induced cardiac fibrosis.

Pericytes are skeletal muscle resident, multipotent stem cells that are localized to capillaries. They respond to damage through activation of nuclear-factor kappa-B (NF-κB), a transcription factor that regulates many cellular processes including inflammation. Research has shown that pericyte NF-κB activation positively affects myoblast proliferation. It is unknown how pericyte NF-κB affects signaling and proliferation of endothelial cells, an important component of muscle tissue microcirculation. PURPOSE: To determine the effects of altered pericyte NF-κB activity on endothelial cell proliferation and identify inflammatory factors involved in this cell-cell signaling. METHODS: Human primary pericytes were transfected with vectors designed to increase or decrease NF-κB activity (or empty vector control). Transfected pericytes were co-cultured with human microvascular endothelial cells (HMVECs) using transwell inserts. HMVEC proliferation was assessed via cell counting at 24 and 48 hr. Secreted cytokines in cell culture supernatants were screened using a Luminex multiplex assay. RESULTS: HMVEC proliferation was greater in the increased pericyte NF-κB activity condition compared to the decreased NF-κB condition at 24 and 48 hr (1.3 fold, p=0.002). At 24 hr, cytokine secretion was greater in the increased NF-κB condition compared to control and decreased NF-κB conditions for 14 cytokines, including interleukin-8 (IL-8; 6.4 fold, p CONCLUSION: NF-κB activation in pericytes caused increased HMVEC proliferation, which may have been mediated by proinflammatory and proangiogenic cytokines known to be under the transcriptional regulation of NF-κB.