The proteinase activated receptor-2 (PAR-2) mediates mitogenic responses in human vascular endothelial cells

The Journal of Clinical Investigation
H MirzaW F Bahou

Abstract

Proteolytically cleaved receptors, typified by the functional thrombin receptor (TR), represent a novel class of receptors that mediate signaling events by functional coupling to G proteins. Northern blot analysis completed with a human proteinase activated receptor-2 (PAR-2) cDNA as probe demonstrated the approximately 3.5kb PAR-2 transcript in total cellular RNA from human umbilical vein endothelial cells (HUVEC). Microspectrofluorimetry using Fura2-loaded HUVEC demonstrated a dose-dependent elevation in intracellular calcium transients ([Ca2+]i) to murine PAR39-44 (SLIGRL, putative neoligand after cleavage), with an approximate EC50 of 30 microM, and evidence for homologous desensitization with complete recovery at 45 min. Xenopus oocytes microinjected with TR cRNA failed to respond to 200 microM PAR39-44, and TR-targeted antisense oligonucleotides specifically abrogated thrombin-induced but not PAR39-44-mediated [Ca2+]i, excluding the possibility that TR/PAR-2 cell-surface coexpression was structurally linked. HUVEC incubated with PAR39-44 demonstrated a dose- and time-dependent mitogenic response similar to that seen with thrombin or TR42-47 (TR-activating peptide, SFLLRN). Preactivation of HUVEC with either PAR39-44 or th...Continue Reading

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