Vascular Rarefaction as a Cause of Diabetic Coronary Microvascular Disease

Cardiovascular disease is the number one cause of death in patients with type 2 diabetes (T2D). Recent studies highlight that T2D also increases the cardiac mortality caused by coronary microvascular disease (CMD). CMD is characterized by a reduced coronary flow reserve, which is typically the result of decreased vasodilation and increased vascular remodeling in small distal coronary arteries and reduced capillary density in the heart. The objective of this study is to compare gender differences in the mechanisms underlining the development of T2D-induced CMD using two types of diabetic mouse models. Inducible T2D (iT2D) mice were generated using a single low-dose injection of streptozotocin (75 mg/kg, i.p.) and a high-fat diet. TALLYHO (TH) mice, a spontaneous T2D mouse model, were purchased from ENVIGO. All experiments were performed 16 weeks after diabetes induction for the iT2D mice and at 16 weeks of age for the TH mice. Age-matched control mice were used to compare the results to diabetic mice. Coronary microvascular function was assessed with coronary flow velocity reserve (CFVR). Coronary endothelial function was evaluated by 1) conducting isometric tension experiments on small coronary arteries (3 rd order) and 2) measuring capillary density and cell apoptosis in the left ventricle. Cardiac endothelial cells (ECs) were isolated for bulk RNA sequencing (RNAseq). Male and female iT2D and TH mouse models exhibit abnormal glucose tolerance. However, fasting glucose levels did not differ between female wild-type (Wt) and female TH mice, suggesting that female TH mice have insulin resistance but not diabetes. All diabetic groups showed a significant decrease in CFVR regardless of the sexes. Male iT2D mice exhibited a significant decrease in endothelium-dependent relaxation (EDR) compared to male controls, while there was no difference between female iT2D and female controls. On the other hand, both male and female TH mice showed a significant decrease in EDR. There is no difference in endothelium-independent relaxation among all groups. There was a significant reduction in capillary density and an increase in apoptotic ECs in iT2D and TH mice regardless of the sexes. These data suggest that the decreased CFVR seen in male iT2D mice, male TH mice, and female TH mice are caused by both attenuated EDR and capillary rarefaction. In contrast, reduced CFVR in female iT2D mice is solely due to capillary rarefaction, suggesting that capillary rarefaction alone may be sufficient to induce CMD. To further understand the molecular mechanisms, RNAseq data in cardiac ECs from male and female control and iT2D mice were collected. The results identified 15 downregulated and 113 upregulated genes in both sexes of iT2D mice. Some of the genes are related to endothelial cell migration, proliferation, angiogenesis, and apoptosis (e.g., Cxcl10, Cxcr4, Dapk1, Daxx, Errfi1, Gja5, Isg, Pml, Ppp1r16b, Tnfaip3, Tspan13, Sema6b, Vegfc ). This suggests that improving capillary density is the potential method to treat CMD in T2D. Supported by NIH R01HL142214 and DOD W81XWH2110472. This abstract was presented at the American Physiology Summit 2025 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.