Abstract Body: Impaired wound healing is a complication of diabetes associated with dysregulated inflammation and poor blood flow at the site of injury. Microvascular ischemia, common in patients with type 2 diabetes (T2D), is a result of impaired endothelial cell function and angiogenesis. Here, we identified that dermal endothelial cells stimulated with TGF-β increased expression of genes encoding pro-angiogenic vascular endothelial growth factor (VEGF) and its primary receptor VEGFR-2. Next, to determine molecular mechanisms by which TGF-β induces VEGF expression, we performed an unbiased gene superarray of chromatin-modifying enzymes on TGF-β-stimulated endothelial cells. This identified p21-activated kinase 1 (Pak1) as the most highly elevated enzyme, increased roughly 2-fold over vehicle-treated cells and confirmed via qPCR. Phosphorylation of histone H3 serine 10, the epigenetic mark of activated Pak1, was increased in western blots of endothelial cells after TGF-β stimulation, while pharmacologic inhibition of Pak1 with 1 μM NVS-PAK1-1 in these cells significantly decreased TGF-β-induced Vegfa gene expression. Notably, stimulation with recombinant VEGF further promoted expression of VEGF and additional angiogenesis-related genes, but Pak1 expression was unaffected, suggesting that VEGF production is elevated downstream of Pak1 activation. Finally, upstream pharmacologic blockade of the TGF-β receptor 1 with 500 nM A83-01 fully inhibited the elevation of Pak1, Vegfa, and Hif1a expression by TGF-β stimulation to vehicle-treated levels, identifying the specific receptor driving this cascade. Together, our results propose a potential mechanism to promote wound angiogenesis via TGF-β/TGF-β receptor 1/PAK1/VEGF signaling Hence, PAK1-mediated epigenetic therapies may improve angiogenesis in T2D wounds and other pathologic conditions where endothelial cell function is impaired.