Role of cyclic AMP-dependent protein kinase A (PKA) in regulation of endothelial barrier during development and homeostasis of vascular system.

Endothelial cells, which cover the internal surface of blood vessels, perform a multitude of functions to maintain homeostasis of our body. One of these functions is to control the passage of solutes and blood cells from the blood into the surrounding tissue - the so called barrier function. The permeability of this barrier changes under physiological and pathological conditions (e.g. injury, wound healing, inflammation, shock, ischemia and cancer). Uncontrolled breakdown of the endothelial barrier or dramatic increase of its permeability is life threatening and pharmacological correction of endothelial barrier function is essential for treatment of conditions such as shock, allergic reaction and edema. However, our understanding of endothelial barrier regulation is far from complete. Here we propose to study animal models of a key mediator of cellular functions - the cAMPdependent protein kinase A (PKA) - in vascular development and function. Using these models, we aim to reveal the cellular and molecular mechanisms of PKA in regulating endothelial barrier function in vivo. Additionally, we will establish whether and how altered endothelial barrier function contributes to defects in vascular development, which occur under the inhibition of endothelial PKA. Successful completion of this work will advance the understanding of the regulation of vascular function and will hopefully uncover new therapeutic opportunities for disease involving vascular dysfunctions.