Cardiovascular diseases (CVDs) such as atherosclerosis and hypertension are the leading causes of morbidity and mortality in our community. Furthermore these vascular complications are accelerated in the diabetic population. Epigenetic mechanisms have been implicated in several common human diseases, including CVDs, due to the influence of the environment which can affect epigenetic states. Evidence shows that the hormone Angiotensin II (Ang II) is a major player in the pathologies of hypertension and atherosclerosis due to its vasoconstrictive, pro-inflammatory, pro-oxidant, and growth promoting effects in target cells such as vascular smooth muscle cells (VSMC). During the previous funding period, we reported the first functional roles for epigenetic chromatin histone modifications and non-coding RNAs in mediating some of these deleterious actions of Ang II in VSMCs. In addition, our new preliminary data show that Ang II can regulate specific novel long non-coding RNAs (lncRNAs), and enhancers in VSMCs that modulate the expression of target genes associated with VSMC inflammation and dysfunction. Despite these advances, the functions of specific lncRNAs and their subtle interactions with other epigenetic factors like enhancers to modulate Ang II-induced gene expression are still not fully understood. Furthermore, the roles of enhancers, superenhancers and specific lncRNAs in Ang II-mediated VSMC dysfunction and related CVDs are not known. Our central hypothesis is that dynamic control of key lncRNAs and VSMC- specific enhancers/superenhancers, as well as epigenetic cross-talk among these factors, contribute to Ang II-induced VSMC dysfunction associated with CVDs. This will be tested through 3 Specific Aims. In Specific Aim 1, we will examine the molecular mechanisms of regulation and functional roles of two novel lncRNAs that we found to be induced by Ang II in VSMCs. In Specific Aim 2, we will define the roles of Ang II-regulated enhancers and superenhancers in the expression of Ang II-regulated genes involved in VSMC functions. In Specific Aim 3, the in vivo expression and functional roles of the two lncRNAs and candidate enhancers/SEs will be examined in mouse models of Ang II induced vascular dysfunction and atherosclerosis. This study examines several new concepts and uses innovative platforms along with functional in vivo models to gain novel insights into VSMC regulatory networks. The results and can have potentially far reaching clinical and therapeutic implications for CVDs.