Download or read book The Implication of Adenylyl Cyclase Isoform 8 and Its Regulation by the Notch Pathway in Vascular Smooth Muscle Cell Transdifferentiation and Pathological Vesel Remodeling written by Zela Talar Keuylian and published by . This book was released on 2013 with total page 178 pages. Available in PDF, EPUB and Kindle. Book excerpt: Atherosclerosis is characterized by the narrowing of the arterial lumen termed "stenosis", due to the expansion of arterial plaques. One of the major contributing factors to the formation of lesions and the neo-intima during post-angioplasty restenosis is the phenotypic change of medial vascular smooth muscle cells. This process switches them from a quiescent/contractile phenotype to a secretory, proliferative, migratory one. My work consisted of elucidating some of the molecular mechanisms implicated in this switch. We showed that the expression of an adenylyl cyclase (AC) isoform, AC8, is implicated in both the inflammatory and migratory properties acquired by trans-differentiated VSMCs. In human atherosclerotic arteries we showed that only intimal VSMCs strongly express AC8; very few AC8 positive VSMCs were detected in the medial layer, either in atherosclerotic or healthy arteries. In the rat balloon injury model of restenosis, we showed a transitory increase of AC8 expression. In vitro, we demonstrated that AC8 expression is regulated by the Notch pathway; inhibiting Notch amplified AC8 expression and decreased Notch target genes Hrt1 and Hrt3. In the same model of restenosis, the transitory up-regulation of AC8 expression coincided with Notch3 down-regulation. These set of experiments demonstrated that the Notch pathway decreases IL1[beta]-mediated AC8 up-regulation in trans-differentiated VSMCs and suggests that AC8 expression, besides being induced by the proinflammatory cytokine IL1[beta],also depends on the down-regulation of the Notch pathway occurring in an inflammatory context. As a whole, my studies attribute a new role for AC8 in pathological vascular remodeling.