Vascular smooth muscle cells (SMCs) play a critical role in intimal hyperplasia in atherosclerosis and restenosis. SMCs in diseased arteries exhibit a modulated phenotype with reduced contractile gene expression, elevated proliferation, and a proinflammatory/profibrotic phenotype. Metabolic reprogramming accompanies and is essential for SMC phenotypic modulation. Our group previously demonstrated that the tumor suppressor gene, PTEN, contributes to the maintenance of the SMC contractile phenotype. Analysis of human GTEx project data established a negative correlation between expression of PTEN and inflammatory genes in human arterial tissues. As a metabolic regulator, the function of PTEN in SMC metabolism has not been examined. We subjected SMC lineage tracing mice with systemic (sPTEN) and inducible, SMC-specific (iPTEN) PTEN overexpression to disease models of atherosclerosis and carotid artery (CA) injury. Compared to control mice, sPTEN and iPTEN mice are protected from atherosclerotic lesion formation and ligation-induced neointima formation. The observed vascular protection effect of PTEN was associated with reduced inflammation and reduced expression of key regulators of glycolysis, including GLUT1, HIF1a and PKM2, which were up-regulated in dedifferentiated SMCs. Consistently, unbiased metabolomics analysis confirmed that CA injury induced a SMC metabolic phenotype, including accumulation of pyruvate, reduction of OXPHOS, and increased fatty acid synthesis, which was rescued in iPTEN mice. Through high throughput screening, we previously identified and validated 5-azacytidine (5-aza) as potent transcriptional activator of PTEN expression. 5-aza reversed injury-induced SMC dedifferentiation in WT, but not PTEN inducible KO (PTEN iKO) mice. Our new scRNA-seq data further suggest that 5-aza inhibited injury-induced SMC metabolic reprogramming and dedifferentiation in a PTEN-dependent manner. Altogether, the data support that PTEN antagonizes the metabolic changes in SMC dedifferentiation and thereby maintains a contractile SMC phenotype. Pharmacological induction of PTEN by 5-aza can serve as a viable approach to rescue SMC metabolic reprogramming and phenotypic modulation in vascular disease.