Reduced MFGE8 Leads to Coronary Microvascular Dysfunction

Coronary microvascular dysfunction (CMD) is a major contributor to ischemic heart disease and is characterized by impaired coronary blood flow in the absence of obstructive coronary artery disease. CMD is highly prevalent in patients with type 2 diabetes (T2D) and is associated with adverse cardiovascular outcomes. Hyperglycemia and dyslipidemia in patients with T2D promote endothelial dysfunction, inflammation, and microvascular remodeling that drive CMD progression. Milk Fat Globule Epidermal Growth Factor 8 (MFGE8) is a secreted glycoprotein involved in apoptotic cell clearance and anti-inflammatory signaling and is implicated in maintaining endothelial and microvascular function. However, the physiological role of MFGE8 in coronary microvascular function and diabetes-mediated CMD remains unclear. In this study, we investigate the physiological role of MFGE8 in coronary endothelial and microvascular function. We utilized 3 different transgenic mice in this study: 1) TALLYHO (TH) mice, a spontaneous polygenic T2D mouse model, 2) systemic Mfge8 knockout (Mfge8-/-) mice, and 3) endothelial cell-specific Mfge8 knockout mice (Cdh5CreERT2-Mfge8-/-). Endothelial-specific gene deletion was induced by tamoxifen injection (50 mg/kg, i.p., 5 days/week, 2 weeks). Experiments were performed at 16 weeks of age for TH and Mfge8-/- mice, and 16 weeks after tamoxifen injection for Cdh5CreERT2-Mfge8-/- mice. All mice were male, and age-matched wild-type mice served as controls. Cardiac endothelial cells (CECs) from T2D patients were obtained from Lonza, and CECs from Wt and TH mice were isolated using CD31-coated magnetic beads. Coronary flow velocity reserve (CFVR, a surrogate measure of coronary microvascular function) was measured using an echocardiograph, and coronary endothelial function was evaluated by isometric tension studies in third-order left coronary arteries. CECs from T2D patients and TH mice showed a significant decrease in MFGE8 protein levels compared with their respective controls. Our TH mice exhibited coronary microvascular dysfunction, evidenced by a significant reduction in CFVR, impaired endothelium-dependent relaxation (EDR), and decreased capillary density. To evaluate the physiological role of MFGE8 in the regulation of coronary microvascular function, we first measured CFVR in Wt and Mfge8-/- mice and found that CFVR was significantly reduced in Mfge8-/- mice. In line with the results from Mfge8-/- mice, Cdh5CreERT2-Mfge8-/- mice also show a significant decrease in CFVR, suggesting that reduced MFGE8 in endothelial cells can lead to CMD. The causes of coronary microvascular dysfunction include increased vasospasm, attenuated endothelium-dependent relaxation, vascular remodeling in small coronary arteries, and decreased capillary density in the heart. Therefore, we assessed and compared EDR in coronary arteries and capillary density in the left ventricle between wild-type mice and Mfge8-deleted mice. Both systemic and endothelial cell-specific Mfge8 knockout mice exhibited impaired EDR and decreased capillary density compared with their controls. In conclusion, MFGE8 plays a critical role in maintaining coronary endothelial and microvascular function, and our data suggest that reduced MFGE8 in cardiac endothelial cells contributes to diabetes-mediated CMD. Future study is required to determine whether increasing MFGE8 levels in diabetic mice can restore coronary endothelial function. This study is supported by NIH R01HL142214 and DOD W81XWH2110472. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.