title: Smooth Muscle-Targeted Overexpression of Peroxisome Proliferator Activated Receptor-γ Disrupts Vascular Wall Structure and Function.
abstract: Activation of the nuclear hormone receptor, PPARγ, with pharmacological agonists promotes a contractile vascular smooth muscle cell phenotype and reduces oxidative stress and cell proliferation, particularly under pathological conditions including vascular injury, restenosis, and atherosclerosis. However, pharmacological agonists activate both PPARγ-dependent and -independent mechanisms in multiple cell types confounding efforts to clarify the precise role of PPARγ in smooth muscle cell structure and function in vivo. We, therefore, designed and characterized a mouse model with smooth muscle cell-targeted PPARγ overexpression (smPPARγOE). Our results demonstrate that smPPARγOE attenuated contractile responses in aortic rings, increased aortic compliance, caused aortic dilatation, and reduced mean arterial pressure. Molecular characterization revealed that compared to littermate control mice, aortas from smPPARγOE mice expressed lower levels of contractile proteins and increased levels of adipocyte-specific transcripts. Morphological analysis demonstrated increased lipid deposition in the vascular media and in smooth muscle of extravascular tissues. In vitro adenoviral-mediated PPARγ overexpression in human aortic smooth muscle cells similarly increased adipocyte markers and lipid uptake. The findings demonstrate that smooth muscle PPARγ overexpression disrupts vascular wall structure and function, emphasizing that balanced PPARγ activity is essential for vascular smooth muscle homeostasis.
authors.affiliation: Atlanta VA Medical Center, Decatur, GA, United States of America; Emory University, Atlanta, GA, United States of America.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Kleinhenz
authors.affiliation: Atlanta VA Medical Center, Decatur, GA, United States of America; Emory University, Atlanta, GA, United States of America.
authors.forename: Tamara C
authors.initials: TC
authors.lastname: Murphy
authors.affiliation: Georgia Institute of Technology, Atlanta, GA, United States of America.
authors.forename: Anastassia P
authors.initials: AP
authors.lastname: Pokutta-Paskaleva
authors.affiliation: Georgia Institute of Technology, Atlanta, GA, United States of America.
authors.forename: Rudolph L
authors.initials: RL
authors.lastname: Gleason
authors.affiliation: Emory University, Atlanta, GA, United States of America.
authors.forename: Alicia N
authors.initials: AN
authors.lastname: Lyle
authors.affiliation: Atlanta VA Medical Center, Decatur, GA, United States of America; Emory University, Atlanta, GA, United States of America; Georgia Institute of Technology, Atlanta, GA, United States of America.
authors.forename: W Robert
authors.initials: WR
authors.lastname: Taylor
authors.affiliation: Emory University, Atlanta, GA, United States of America.
authors.forename: Mitsi A
authors.initials: MA
authors.lastname: Blount
authors.affiliation: Emory University, Atlanta, GA, United States of America.
authors.forename: Juan
authors.initials: J
authors.lastname: Cheng
authors.affiliation: University of Alabama at Birmingham, Birmingham, AL, United States of America.
authors.forename: Qinglin
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Atlanta VA Medical Center, Decatur, GA, United States of America; Emory University, Atlanta, GA, United States of America.
authors.forename: Roy L
authors.initials: RL
authors.lastname: Sutliff
authors.affiliation: Atlanta VA Medical Center, Decatur, GA, United States of America; Emory University, Atlanta, GA, United States of America.
authors.forename: C Michael
authors.initials: CM
authors.lastname: Hart
mesh_terms: D000818:Animals; D001011:Aorta / Q000033:anatomy & histology / Q000166:cytology / Q000502:physiology*; D001794:Blood Pressure; D002460:Cell Line; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D014661:Vasoconstriction; D014664:Vasodilation
chemical_list: D047495:PPAR gamma