Cellular crosstalk in organotypic vasculature: mechanisms of diabetic cardiorenal complications and SGLT2i responses

Diabetic panvascular disease (DPD) is the leading clinical complication of diabetes mellitus (DM), characterized by atherosclerosis across multiple organ vessels. It is a major cause of high disability and mortality rates in DM. However, the pathological mechanisms and key mediators of DPD remain unclear. This study constructed a single-cell organotypic atlas of the vasculature containing 321,358 cells by integrating 14 single-cell datasets from 8 major mouse organs and tissues. A total of 63 cell types were identified, including 9 vascular cell subtypes, whereas the cell-to-cell interaction (CCI) patterns of the organotypic vasculature were systematically analyzed. Endothelial cells (ECs) were identified as the major cell type involved in CCI within the vasculature, with their ligands interacting with receptors of various cell types, which contribute to multiple biological processes such as stem cell differentiation and immune regulation. Notably, the study examined the cellular communication characteristics of different EC subtypes. Additionally, the inter-organ communication between the heart and kidney—key tissues in DPD—was analyzed. The BMP signaling pathway emerged as a critical communication pathway leading to cardiorenal complications in DM, with SGLT2i having a regulatory role in BMP6 modulation. The study provides, for the first time, a single-cell analysis of the CCI patterns of the organotypic vasculature and highlights the central role of ECs. Moreover, the key role of BMP6 in diabetic cardiorenal complications is elucidated. These findings offer new insights into the mechanisms underlying DPD co-morbidities and provide a novel scientific basis for clinical prevention, treatment strategies for DPD, and the understanding of the action mechanism of SGLT2i.