Spatial Transcriptomic Profiling of the Type 2 Diabetic Coronary Microcirculation Varied by Regions of the Heart

Coronary microvascular disease (CMD) is an early complication of type 2 diabetes (T2D) that arises from the dysfunction of endothelial and vascular smooth muscle cells (VSMCs), along with remodeling of the walls of the coronary resistance microvessels (CRMs). CRMs from T2D mice and pigs are less stiff compared to normal, a finding that is dictated by less stiff coronary VSMCs. These data suggest that cell- and vascular layer-specific mechanisms are responsible for CMD. To interrogate these mechanisms, we hypothesized that spatial transcriptomic analysis of the CRM layers can identify new pathways to target in CMD. 16-week-old control Db/db (n=4) and T2D db/db (n=3) mouse hearts were collected, fixed, embedded, sectioned onto Visium reaction slides (10X Genomics). Libraries were generated using the 10X Visium Spatial Gene Expression for FFPE kit. Data were analyzed with Seurat. We next selected CRM-enriched spots in 5 regions of the heart: left ventricular (LV) anterior wall (AW), LV free wall (FW), LV posterior wall (PW), LV septum, and right ventricle (RV). In the LVAW, Fabp3, Ech1, Myom2, Decr1, Slc25a20, and Acaa2 were all significantly higher in the T2D CRMs of that region whereas C7, Cd74, and B2m were significantly decreased. Interestingly, in the LVFW Fabp3, Ech1, Decr1 were also significantly increased as well as Slc8a1 in the db/db CRMs. B2m was the only significantly decreased gene in the db/db LVFW. Ucp2 was significantly increased in the db/db LVPW. In the LV septum, Fabp3 was significantly increased in the db/db CRMs. Interestingly, the most pronounced transcriptional differences between diabetic and control CRMs appeared to be within the LV anterior wall, where we observed a downregulation of many pathways associated with inflammatory response in the diabetic mice (e.g. interferon alpha response, leukocyte proliferation, immune response, interleukin 1 production, and chemokine production). Other significantly different pathways that were enriched in LVAW between diabetic and control samples in the CRMs included increased hallmark oxidative phosphorylation, increased hallmark fatty acid metabolism implicated mitochondrial dysfunction. These data demonstrate novel transcriptomic differences in CRMs within spatially-distinct regions of the T2D heart. Continuing analysis will identify specific molecular targets involved in the pathophysiology of CMD with the goal of identifying novel therapeutic targets. R01 HL165124 and S10 OD023438 and internal NCH funds to AJT. 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.