phaidra.vetmeduni.ac.at o:4446 DOI 10.3390/ijms25115929 Ablation of Vitamin D Signaling in Cardiomyocytes Leads to Functional Impairment and Stimulation of Pro-Inflammatory and Pro-Fibrotic Gene Regulatory Networks in a Left Ventricular Hypertrophy Model in Mice 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. eng Vitamin D Vitamin D Receptor Left Ventricular Hypertrophy Cardiomyocytes Spatial Transcriptomics Inflammation Fibrosis 2025-10-06T14:01:23.048Z LOMv1.0 Author BEGIN:VCARD VERSION:3.0 N:Zupcic;Ana; FN:Ana Zupcic END:VCARD BEGIN:VCARD VERSION:3.0 N:Latic;Nejla; FN:Nejla Latic X-ORCID:https://orcid.org/0000-0001-5635-5175 END:VCARD BEGIN:VCARD VERSION:3.0 N:Oubounyt;Mhaned; FN:Mhaned Oubounyt END:VCARD BEGIN:VCARD VERSION:3.0 N:Ramesova;Alice; FN:Alice Ramesova X-ORCID:https://orcid.org/0000-0001-7482-7818 END:VCARD BEGIN:VCARD VERSION:3.0 N:Carmeliet;Geert; FN:Geert Carmeliet END:VCARD BEGIN:VCARD VERSION:3.0 N:Baumbach;Jan; FN:Jan Baumbach END:VCARD BEGIN:VCARD VERSION:3.0 N:Elkjaer;Maria L; FN:Maria L Elkjaer END:VCARD BEGIN:VCARD VERSION:3.0 N:Erben;Reinhold G; FN:Reinhold G Erben X-ORCID:https://orcid.org/0000-0003-0801-6958 END:VCARD https://w3id.org/kim/hcrt/scheme https://w3id.org/kim/hcrt/text Textdokument Text LOMv1.0 yes https://creativecommons.org/licenses/by/4.0 application/pdf 3373554 https://phaidra.vetmeduni.ac.at/o:4446 https://phaidra.vetmeduni.ac.at/api/object/o:4446/thumbnail LOMv1.0 discipline