Figure 3: Proposed model depicting the ameliorative role of PACAP in hyperglycemia-induced endothelial dysfunction: potential involvement of smooth muscle cells through a paracrine mechanism. One of the most devastating complications of persistent hyperglycemia is micro- and macroangiopathy that may determine abnormal vasculogenesis. However, the exact pathogenetic mechanisms are still not well understood. In the proposed scenario, longstanding high glucose levels in the blood stream cause both mechanical (shear stress) or oxidative injury (↑ ROS production) to endothelial cells, whose in turn react by triggering local inflammatory responses, sustained PKC activation, and aberrant angiogenesis (↑ endothelial cell proliferation). PACAP seems to play a homeostatic role in this process. Once released by the neighboring smooth muscle cells (SMCs) it binds to PAC1 receptors expressed by both endothelial cells and SMCs, thereby activating a cAMP-driven signalling cascade that inhibits glucose-induced proliferation of both cell populations and ROS production and dampens PKC function as well as local release of proinflammatory cytokines by infiltrating macrophages.