PALMD haploinsufficiency aggravates extracellular matrix remodeling in vascular smooth muscle cells and promotes calcification

Reduced PALMD expression is strongly associated with the development of calcified aortic valve stenosis; however, the role of PALMD in vascular calcification remains unknown. Calcified arteries were collected from mice to detect PALMD expression. Heterozygous <i>Palmd</i> knockout (<i>Palmd</i>^+/-) mice were established to explore the role of PALMD in subtotal nephrectomy-induced vascular calcification. RNA sequencing was applied to detect molecular changes in aortas from <i>Palmd</i>^+/- mice. Primary <i>Palmd</i>^+/- vascular smooth muscle cells (VSMCs) or PALMD-silenced VSMCs by short interfering RNA were used to analyze PALMD function in phenotypic changes and calcification. PALMD haploinsufficiency aggravated subtotal nephrectomy-induced vascular calcification. RNA sequencing analysis showed that loss of PALMD disturbed the synthesis and degradation of the extracellular matrix (ECM) in aortas, including collagens and matrix metalloproteinases (<i>Col6a6</i>, <i>Mmp2</i>, <i>Mmp9</i>, etc.). In vitro experiments revealed that PALMD-deficient VSMCs were more susceptible to high phosphate-induced calcification. Downregulation of SMAD6 expression and increased levels of p-SMAD2 were detected in <i>Palmd</i>^+/- VSMCs, suggesting that transforming growth factor-β signaling may be involved in PALMD haploinsufficiency-induced vascular calcification. Our data revealed that PALMD haploinsufficiency causes ECM dysregulation in VSMCs and aggravates vascular calcification. Our findings suggest that reduced PALMD expression is also linked to vascular calcification, and PALMD may be a potential therapeutic target for this disease. <b>NEW & NOTEWORTHY</b> We found that PALMD haploinsufficiency causes extracellular matrix dysregulation, reduced PALMD expression links to vascular calcification, and PALMD mutations may lead to the risk of both calcific aortic valve stenosis and vascular calcification.