Endothelial dysfunction is the initiation factor for the onset of cardiovascular diseases and is characterized by increased expression of endothelial cell adhesion molecules (ICAM-1 and VCAM-1), ROS production, inflammation, and reduced bioavailability of nitric oxide (NO). Insulin resistance and subsequent compensatory hyperinsulinemia are one of the major risk factors for endothelial dysfunction which blunts the PI3-K/Akt pathway and reduces NO production in endothelial cells. Studies have demonstrated that protein tyrosine phosphatases are the negative regulators of insulin signaling. However, the role of protein tyrosine phosphatase- PEST (also known as PTPN12) in insulin/hyperinsulinemia mediated endothelial response is currently unknown. PTP- PEST, a ubiquitously expressed enzyme is reported to regulate various processes such as integrin-mediated cell adhesion, migration, and tumor suppression by dephosphorylating selective substrates. Loss of PTP-PEST (either global or in the endothelium) results in vasculogenic defects and embryonic lethality. Recent studies from our lab have shown that PTPN12 activates AMPK, an energy sensing enzyme. Studies have also shown that PI3-K/Akt pathway negatively regulates AMPK demonstrating a cross talk between AMPK and insulin signaling. The aim of my study is to determine whether PTP- PEST has any role in insulin or hyperinsulinemia mediated signaling in endothelial cells and how it regulates endothelial function.