title: Alpha1a-Adrenoceptor Genetic Variant Triggers Vascular Smooth Muscle Cell Hyperproliferation and Agonist Induced Hypertrophy via EGFR Transactivation Pathway.
abstract: α1a Adrenergic receptors (α1aARs) are the predominant AR subtype in human vascular smooth muscle cells (SMCs). α1aARs in resistance vessels are crucial in the control of blood pressure, yet the impact of naturally occurring human α1aAR genetic variants in cardiovascular disorders remains poorly understood. To this end, we present novel findings demonstrating that 3D cultures of vascular SMCs expressing human α1aAR-247R (247R) genetic variant demonstrate significantly increased SMC contractility compared with cells expressing the α1aAR-WT (WT) receptor. Stable expression of 247R genetic variant also triggers MMP/EGFR-transactivation dependent serum- and agonist-independent (constitutive) hyperproliferation and agonist-dependent hypertrophy of SMCs. Agonist stimulation reduces contractility Using pathway-specific inhibitors we determined that the observed hyperproliferation of 247R-expressing cells is triggered via β-arrestin1/Src/MMP-2/EGFR/ERK-dependent mechanism. MMP-2-specific siRNA inhibited 247R-triggered hyperproliferation indicating MMP-2 involvement in 247R-triggered hyperproliferation in SMCs. β-arrestin1-specific shRNA also inhibited 247R-triggered hyperproliferation but did not affect hypertrophy in 247R-expressing SMCs, indicating that agonist-dependent hypertrophy is independent of β-arrestin1. Our data reveal that in different cardiovascular cells the same human receptor genetic variant can activate alternative modulators of the same signaling pathway. Thus, our findings in SMCs demonstrate that depending on the type of cells expressing the same receptor (or receptor variant), different target-specific inhibitors could be used to modulate aberrant hyperproliferative or hypertrophic pathways in order to restore normal phenotype.
authors.affiliation: Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Irina
authors.initials: I
authors.lastname: Gradinaru
authors.affiliation: Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Babaeva
authors.affiliation: Department of Anesthesiology, University of Iowa, Iowa City, Iowa, United States of America.|Department of Pharmacology, University of Iowa, Iowa City, Iowa, United States of America.|Department of Biochemistry, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Debra A
authors.initials: DA
authors.lastname: Schwinn
authors.affiliation: Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Anush
authors.initials: A
authors.lastname: Oganesian
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D019390:Arrestins / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D014644:Genetic Variation; D006801:Humans; D006984:Hypertrophy; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects*; D000071557:beta-Arrestins; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D019390:Arrestins; D018340:Receptors, Adrenergic, alpha-1; D000071557:beta-Arrestins; D066246:ErbB Receptors; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020782:Matrix Metalloproteinases