Cardiovascular disease most commonly presents as an arterial occlusion due to the presence of atherosclerotic lipid plaques. Typically, balloon angioplasty is subsequently performed to remove the plaque and restore blood supply to ischaemic tissue. Despite the increased use of metal stents to maintain lumen diameter, re-occlusion still occurs in approximately 30% of cases. This re-occlusion is the result of arterial hyperplasia predominantly due to increased vascular smooth muscle (VSM) cell proliferation. The primary mechanisms which initiate this proliferation are not clear but probably involve regulation at the transcriptional level. An important event in the modulation of VSM cells to a proliferative phenotype is the active repression of smooth muscle (SM) marker proteins associated with contractility, such as calponin and SM α-actin. This decrease in SM marker proteins is controlled by growth factors via activation of the mitogen-activated protein kinases, extracellular signal-regulated kinase (ERK)1/2. When an appropriate growth signal is received by the VSM cell, this leads to phosphorylation of ERK1/2 which in turn regulates specific transcription factors including Elk-1. Elk-1 has a critical role in gene expression and in VSM cells is responsible for repressing SM marker genes. We recently revealed a novel mechanism regulating ERK1/2 and subsequently Elk-1 in VSM cells which is likely to be important in regulating VSM cell proliferation. An essential step in ERK1/2-induced changes in gene expression is the translocation of ERK1/2 from the cytoplasm to the nucleus. The ability of growth factors to repress SM marker genes is inhibited (and proliferation is decreased) if ERK1/2 nuclear translocation is prevented in VSM cells. Our experimental evidence indicates that a protein previously uncharacterized in VSM cells, phosphoprotein enriched in astrocytes-15 (PEA-15), has an essential role in regulating ERK1/2 nuclear localization. PEA-15 has a cytoplasmic distribution (courtesy of a nuclear export sequence) and one of its primary roles is to function as an ERK1/2-binding protein (Greig and Nixon, 2014). We have confirmed that PEA-15 binds and sequesters ERK1/2 in the cytoplasm in VSM cells. Furthermore, in cultured human coronary artery VSM cells, knockdown of PEA-15 results in ERK1/2 nuclear localization, which can be reversed by PEA-15 overexpression (Hunter et al, 2011). During physiological stimulation by growth factors in VSM cells, ERK1/2 can only be released from PEA-15 when PEA-15 is phosphorylated. This occurs via growth factor-induced activation of protein kinase C and Ca2+/calmodulin-dependent protein kinase II. This PEA-15 phosphorylation is required for growth factor-induced VSM cell proliferation. PEA-15 therefore has a critical role in VSM cell physiology. As PEA-15 has an important role in regulating VSM cell proliferation, changes in PEA-15 expression could have profound effects on blood vessel structure and function. Specifically in vascular disease, such as arterial hyperplasia, decreased PEA-15 expression would result in increased ERK1/2 nuclear localization and potentially increased proliferation. We have now examined PEA-15 expression using an in vivo vascular injury mouse model. Following wire injury of the mouse carotid artery, PEA-15 expression was determined at different timepoints post-surgery. Our results reveal a significantly decreased PEA-15 expression at 3 days post-injury compared to control arteries. Importantly this occurs before hyperplasia is observed. PEA-15 expression in arteries returns to normal at day 7 post-injury. Similar results for PEA-15 expression were also obtained in an ex vivo model of vascular injury using human saphenous vein.In conclusion, the phosphoprotein PEA-15 has an important role in VSM cell biology. It acts as a switch to regulate cell phenotype and may also be involved in the pathogenesis of vascular disease.