The Confluence-dependent Interaction of Cytosolic Phospholipase A2-α with Annexin A1 Regulates Endothelial Cell Prostaglandin E2 Generation

Abstract

The regulated generation of prostaglandins from endothelial cells is critical to vascular function. Here we identify a novel mechanism for the regulation of endothelial cell prostaglandin generation. Cytosolic phospholipase A 2 -␣ (cPLA 2 ␣) cleaves phospholipids in a Ca 2؉ -dependent manner to yield free arachidonic acid and lysophospholipid. Arachidonic acid is then converted into prostaglandins by the action of cyclooxygenase enzymes and downstream synthases. By previously undefined mechanisms, nonconfluent endothelial cells generate greater levels of prostaglandins than confluent cells. Here we demonstrate that Ca 2؉-independent association of cPLA 2 ␣ with the Golgi apparatus of confluent endothelial cells correlates with decreased prostaglandin synthesis. Golgi association blocks arachidonic acid release and prevents functional coupling between cPLA 2 ␣ and COX-mediated prostaglandin synthesis. When inactivated at the Golgi apparatus of confluent endothelial cells, cPLA 2 ␣ is associated with the phospholipid-binding protein annexin A1. Furthermore, the siRNA-mediated knockdown of endogenous annexin A1 significantly reverses the inhibitory effect of confluence on endothelial cell prostaglandin generation. Thus the confluence-dependent interaction of cPLA 2 ␣ and annexin A1 at the Golgi acts as a novel molecular switch controlling cPLA 2 ␣ activity and endothelial cell prostaglandin generation.

C2 domain membrane penetration by group IVA cytosolic phospholipase A2 induces membrane curvature changes

“…cPLA 2 ␣ has been shown to function in generation of cholesterolrich, GPI protein-containing endosomes ( 26 ), Golgi tubulation and vesiculation ( 24,25 ), and Golgi-to-PM traffi cking ( 60 ). Additionally, cPLA 2 ␣ association with the Golgi has been shown to regulate the function of endothelial cells ( 61,62 ), which serve a barrier function in the luminal surfaces of blood vessels. Proliferation of endothelial cells has been shown to occur for the formation of blood vessels in wound healing and tumor formation while blocking cPLA 2 ␣ activity through an inhibitor or siRNA blocks endothelial cell proliferation and cell cycle entry ( 61 ).…”

Low abundance plasma proteins in labour

“…Therefore, the decrease of ANXA1 in the plasma of IoL supports the idea that medical IoL may provoke excess activation of inflammatory pathways. In addition, a decrease of ANXA1 expression can result in liberation of phospholipase A2 activity, making more arachidonic acid available for prostaglandin generation (Herbert et al 2007), which is crucial in uterine contraction.…”

Comparative analysis of annexin-1 in neuroepithelial tumors shows altered expression with the grade of malignancy but is not associated with survival

“…The functional role of annexin-1 in the vessels is not well understood, but a protective role is proposed. 28 This consistent pattern serves as a good internal control in the otherwise immunonegative tumor specimens. In addition, we show that the annexin-1 expression levels significantly increase with WHO grade in diffuse astrocytomas.…”