Going With The Flow: Selective phosphodiesterase 4D7 (PDE4D7) regulation of vascular endothelial cell responses to fluid shear stress

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Burke-Kleinman, Jonah
endothelial , cardiovascular , signalling , heart disease , fluid shear stress
Vascular endothelial cells (VECs) regulate their phenotype in response to the frictional force exerted by the flowing blood, fluid shear stress (FSS). The hemodynamics dictating this force determine, to a large extent, the likelihood that a given region of a blood vessel will develop atherosclerotic plaque. In linear arterial segments, VECs are exposed to high laminar unidirectional FSS (15-20 dyne/cm2), whereas in bifurcations, arches and branch points, VECs encounter low magnitude/oscillating or otherwise disturbed FSS (0-4 dyne/cm2). High laminar FSS promotes establishment of an adaptive VEC phenotype, characterized by the expression of anti-thrombotic, anti-inflammatory and anti- atherogenic genes. Conversely, low and oscillating flow causes VECs to express pro-inflammatory, pro-thrombotic genes and adopt an athero-prone phenotype. Previous studies have identified mechanosensory signalling molecules that allow VECs to sense and respond to FSS, which include vascular endothelial cadherin (VE-cadherin), platelet endothelial cell adhesion molecule 1 (PECAM- 1) and vascular endothelial growth factor receptor 2 (VEGFR2). Research conducted by our group has previously shown that exchange protein activated by cAMP (EPAC1) and cyclic nucleotide phosphodiesterase 4D (PDE4D) populate a multi-protein signalling complex along with VE- cadherin. These proteins function together to regulate VEC barrier function, cell morphology and gene expression of in response to FSS. Now, we have investigated this compartmentalized signalling complex in greater detail, and have identified that one splice variant, namely phosphodiesterase 4D7 (PDE4D7), controls VEC gene regulation in response to FSS, while another, PDE4D5, does not. Indeed, we show that PDE4D7 silencing with siRNA attenuates the upregulation of krüppel-like factor 2 (KLF2), endothelial nitric oxide synthase (eNOS) and thrombomodulin (TM) in VECs exposed to FSS. This work identifies a potential novel specific therapeutic target for the treatment or prevention of atherosclerosis and improves our understanding of mechanosensory signal transduction in the vascular endothelium.
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