Regulation of vascular endothelial cells and vascular smooth muscle cells by multiple P2Y receptor subtypes

Abstract

Receptors for nucleotides regulate all aspects of vascular function. Here, the role and function of P2Y receptors in vascular endothelium and smooth muscle cell proliferation are explored. In both cell types the presence of multiple P2Y receptors is commonplace; however, the identity and role of these receptors is dependent on the vessel of origin. This is clearly seen with endothelial cells. The commonest observation is coexisting P2Y 1 and P2Y 2 (or P2Y 4 ) receptors coupled through inositol 1,4,5-trisphosphate production to Ca 2+ mobilisation. However, in some endothelial cells other P2Y receptors are present. Brain microvascular endothelial cells, for example, exhibit a variety of responses with profiles which cannot be fully explained by cloned P2Y receptors, and which are coupled to diverse receptor-effector mechanisms. These include p42/p44 mitogen-activated protein kinase activation, enhanced cyclic AMP synthesis and raised cytosolic Ca 2+ in the absence of detectable rises in inositol 1,4,5-trisphosphate. These responses can be expected to influence endothelial prostacyclin and nitric oxide production, permeability, adhesion factor expression, and leukocyte-endothelial interaction. P2Y receptors also regulate proliferative responses. Previously, data has been presented indicating that nucleotides acting on P2Y receptors can enhance cell proliferation in response to other agents. Here, we discuss evidence that UTP is an antiproliferative regulator in human vascular smooth muscle cells and that P2Y 4 receptors may be involved in this response. Drug Dev.

Purinergic Signaling and Blood Vessels in Health and Disease

“…UTP and UDP have been claimed to induce rat aortic smooth muscle cell migration via P2Y 2 and P2Y 6 receptors, respectively (Pillois et al, 2002). Antiproliferative effects of UTP on cultured vascular smooth muscle cells derived from human internal mammary artery and saphenous vein have been claimed (White et al, 2000;Boarder et al, 2001). More recently, P2X 1 receptors were shown to mediate inhibition of proliferation of human coronary artery smooth muscle cells via induction of the transcription factor NR4A1 (Hinze et al, 2013).…”

“…However, adenosine, via A 2B receptors, has been reported to inhibit growth of rat and human aortic smooth muscle cells (Dubey et al, 1996(Dubey et al, , 1998Jackson et al, 2011). Strong effects of adenosine on gene induction in human coronary artery vascular smooth muscle cells via A 2B receptors have been described associated with the antiproliferative effects of adenosine (White et al, 2000;Boarder et al, 2001). b Pulmonary artery (hypertension and smooth muscle proliferation in A 2A receptor knockouts) .…”