title: Receptor for Advanced Glycation End-Products Signaling Interferes with the Vascular Smooth Muscle Cell Contractile Phenotype and Function.
abstract: Increased blood glucose concentrations promote reactions between glucose and proteins to form advanced glycation end-products (AGE). Circulating AGE in the blood plasma can activate the receptor for advanced end-products (RAGE), which is present on both endothelial and vascular smooth muscle cells (VSMC). RAGE exhibits a complex signaling that involves small G-proteins and mitogen activated protein kinases (MAPK), which lead to increased nuclear factor kappa B (NF-κB) activity. While RAGE signaling has been previously addressed in endothelial cells, little is known regarding its impact on the function of VSMC. Therefore, we hypothesized that RAGE signaling leads to alterations in the mechanical and functional properties of VSMC, which could contribute to complications associated with diabetes. We demonstrated that RAGE is expressed and functional in the A7r5 VSMC model, and its activation by AGE significantly increased NF-κB activity, which is known to interfere with the contractile phenotype of VSMC. The protein levels of the contraction-related transcription factor myocardin were also decreased by RAGE activation with a concomitant decrease in the mRNA and protein levels of transgelin (SM-22α), a regulator of VSMC contraction. Interestingly, we demonstrated that RAGE activation increased the overall cell rigidity, an effect that can be related to an increase in myosin activity. Finally, although RAGE stimulation amplified calcium signaling and slightly myosin activity in VSMC challenged with vasopressin, their contractile capacity was negatively affected. Overall, RAGE activation in VSMC could represent a keystone in the development of vascular diseases associated with diabetes by interfering with the contractile phenotype of VSMC through the modification of their mechanical and functional properties.
authors.affiliation: Département de Pharmacologie et physiologie, Faculté de Médecine et des Sciences de la Santé de l'Université de Sherbrooke, Sherbrooke, Canada.
authors.forename: Elie
authors.initials: E
authors.lastname: Simard
authors.affiliation: Département de Pharmacologie et physiologie, Faculté de Médecine et des Sciences de la Santé de l'Université de Sherbrooke, Sherbrooke, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Söllradl
authors.affiliation: Département de Pharmacologie et physiologie, Faculté de Médecine et des Sciences de la Santé de l'Université de Sherbrooke, Sherbrooke, Canada.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Maltais
authors.affiliation: Département de Pharmacologie et physiologie, Faculté de Médecine et des Sciences de la Santé de l'Université de Sherbrooke, Sherbrooke, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Boucher
authors.affiliation: Département de Pharmacologie et physiologie, Faculté de Médecine et des Sciences de la Santé de l'Université de Sherbrooke, Sherbrooke, Canada; Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, Canada.
authors.forename: Pédro
authors.initials: P
authors.lastname: D'Orléans-Juste
authors.affiliation: Département de Pharmacologie et physiologie, Faculté de Médecine et des Sciences de la Santé de l'Université de Sherbrooke, Sherbrooke, Canada; Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, Canada; Chaire de Recherche Canadienne en Nanopharmacologie et Microscopie à Force Atomique, Faculté de Médecine et des Sciences de la Santé de l'Université de Sherbrooke, Sherbrooke, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Grandbois
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D048909:Diabetes Complications / Q000209:etiology / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006801:Humans; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism*; D012709:Serum Albumin / Q000378:metabolism; D015398:Signal Transduction; D014652:Vascular Diseases / Q000209:etiology / Q000378:metabolism; D000093423:Glycated Serum Albumin
chemical_list: D017127:Glycation End Products, Advanced; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D012709:Serum Albumin; D002118:Calcium; D000093423:Glycated Serum Albumin