Ana Zupcic Ana Zupcic Nejla Latic Nejla Latic Mhaned Oubounyt Mhaned Oubounyt Alice Ramesova Alice Ramesova Geert Carmeliet Geert Carmeliet Jan Baumbach Jan Baumbach Maria L Elkjaer Maria L Elkjaer Reinhold G Erben Reinhold G Erben MDPI 2024 The association between vitamin D deficiency and cardiovascular disease remains a controversial issue. This study aimed to further elucidate the role of vitamin D signaling in the development of left ventricular (LV) hypertrophy and dysfunction. To ablate the vitamin D receptor (VDR) specifically in cardiomyocytes, VDRfl/fl mice were crossed with Mlcv2-Cre mice. To induce LV hypertrophy experimentally by increasing cardiac afterload, transverse aortic constriction (TAC) was employed. Sham or TAC surgery was performed in 4-month-old, male, wild-type, VDRfl/fl, Mlcv2-Cre, and cardiomyocyte-specific VDR knockout (VDRCM-KO) mice. As expected, TAC induced profound LV hypertrophy and dysfunction, evidenced by echocardiography, aortic and cardiac catheterization, cardiac histology, and LV expression profiling 4 weeks post-surgery. Sham-operated mice showed no differences between genotypes. However, TAC VDRCM-KO mice, while having comparable cardiomyocyte size and LV fibrosis to TAC VDRfl/fl controls, exhibited reduced fractional shortening and ejection fraction as measured by echocardiography. Spatial transcriptomics of heart cryosections revealed more pronounced pro-inflammatory and pro-fibrotic gene regulatory networks in the stressed cardiac tissue niches of TAC VDRCM-KO compared to VDRfl/fl mice. Hence, our study supports the notion that vitamin D signaling in cardiomyocytes plays a protective role in the stressed heart. PDFDocument eng 2025-10-06T14:01:22.786577Z 2024 Vitamin D Vitamin D Receptor Left Ventricular Hypertrophy Cardiomyocytes Spatial Transcriptomics Inflammation Fibrosis 3373554 b application/pdf http://creativecommons.org/licenses/by/4.0/