Soluble fms-like tyrosine kinase-1 and angiotensin2 target CALCB family peptides in maternal vascular smooth muscle cells in pregnancy.

Effect of fms-like tyrosine kinase (sFLT-1) and angiotensin2 (Ang2) on the function of calcitonin gene-related peptide (CALCB), adrenomedullin (ADM) and adrenomedullin2 (ADM2) in vascular smooth muscle cell, and the effect of preeclampsia (PE) on the sensitivity of omental artery (OA) for these peptides is not known in human pregnancy. OBJECTIVE Identify the effect of sFLT-1 and Ang2 on the function of CALCB family peptides in OA smooth muscle cells (OASMC) and assess the sensitivity of OA for these peptides in PE and normotensive pregnancy. METHODS Peptide function was assessed by cAMP assays and wire myograph; mRNA expression by PCR and protein-protein interaction by proximity ligation assay and co-immunoprecipitation. FINDINGS All 3 peptides increased cAMP synthesis in the order of efficacy CALCB>ADM = ADM2 and VEGF mRNA in OASMC (p < 0.05); sFLT-1 mediated decrease in cAMP synthesis (p < 0.05) is differentially rescued by all 3 CALCB family peptides in OASMC (P < 0.005); sFLT-1 decreased receptor activity modifying protein (RAMP)1 and RAMP2 mRNA expression (p < 0.05); Ang2 decreased the expression of CALCRL and RAMP1 mRNA and desensitized CALCB and ADM2 receptors in OASMC (p < 0.05); sFLT-1 increased RAMP1and Ang2 type 1 receptor (AT1R) interaction in OASMC which is inhibited in presence of all 3 peptides; and all 3 peptides relax OA in PE with enhanced ADM2 response (p < 0.05). CONCLUSION sFLT-1 and Ang2 impair OASMC mediated functional responses of CALCB family peptides which can be inhibited by respective peptide treatment. The sensitivity of OA for CALCB, ADM and ADM2-mediated relaxation is retained in PE.