Mutations in theLMNAgene (encoding lamin A/C proteins) cause several human cardiac diseases, including dilated cardiomyopathies (LMNA-DCM). The main clinical risks inLMNA-DCM patients are sudden cardiac death and progressive left ventricular ejection fraction deterioration, and therefore most human and animal studies have sought to define the mechanisms through whichLMNAmutations provoke cardiac alterations, with a particular focus on cardiomyocytes. To investigate ifLMNAmutations also cause vascular alterations that might contribute to the etiopathogenesis ofLMNA-DCM, we generated and characterizedLmnaflox/floxSM22αCremice, which constitutively lack lamin A/C in vascular smooth muscle cells (VSMCs), cardiac fibroblasts, and cardiomyocytes. Like mice with whole body or cardiomyocyte-specific lamin A/C ablation,Lmnaflox/floxSM22αCremice recapitulated the main hallmarks of humanLMNA-DCM, including ventricular systolic dysfunction, cardiac conduction defects, cardiac fibrosis, and premature death. These alterations were associated with elevated expression of total and phosphorylated (active) Smad3 and cleaved (active) caspase 3 in the heart.Lmnaflox/floxSM22αCremice also exhibited perivascular fibrosis in the coronary arteries and a switch of aortic VSMCs from the ‘contractile’ to the ‘synthetic’ phenotype. Ex vivo wire myography in isolated aortic rings revealed impaired maximum contraction capacity and an altered response to vasoconstrictor and vasodilator agents inLmnaflox/floxSM22αCremice. To our knowledge, our results provide the first evidence of phenotypic alterations in VSMCs that might contribute significantly to the pathophysiology of some forms ofLMNA-DCM. Future work addressing the mechanisms underlying vascular defects inLMNA-DCM may open new therapeutic avenues for these diseases.