Atherosclerosis is a progressive disease that is a leading cause of death in the Western world. Remarkably, despite decades of research, there remain major ambiguities regarding the role of smooth muscle cells (SMC) in lesion pathogenesis, as well as mechanisms that control plaque stability and the probability of plaque rupture with possible myocardial infarction (MI) or stroke. The general dogma is that SMC are primarily involved in late not early stage lesions, and that their primary role is atheroprotective by contributing to formation of a fibrous cap. However, recent Nature Medicine studies by our lab involving simultaneous SMC-specific lineage tracing and knockout (KO) of the stem cell pluripotency genes, Oct4 or Klf4 provided compelling evidence that SMC play a much greater role in lesion pathogenesis than has been generally appreciated. Key findings include our showing that: 1) >80% of SMC-derived cells within advanced lesions of ApoE-/- mice lack detectable expression of typical SMC markers; 2) 30-40% of SMC-derived cells within both advanced mouse and human lesions lack detectable SMC markers and have activated markers of M?s; and 3) SMC can have major beneficial or detrimental effects on lesion pathogenesis depending on the nature of their phenotypic transitions. Thus, there is a critical need to identify factors and mechanisms that promote beneficial changes in SMC phenotype. Studies in this proposal will test the overall hypothesis that PDGF?R-dependent changes in SMC phenotype are atheroprotective and that augmentation of the PDGF?R signaling pathway should be one of the primary therapeutic targets for treating advanced atherosclerosis. This hypothesis will be tested in two specific aims.
Aim 1 will test the hypothesis that PDGF?R- dependent transitions in SMC phenotypic play a critical role in the development and progression of atherosclerosis.
Aim 1 a will extend our initial studies showing that SMC specific conditional PDGF?R KO at 6-8 weeks of age followed by 18 weeks of Western diet (WD) resulted in BCA lesions that were larger but virtually lacking SMC to include rigorous analysis of indices of plaque stability and mechanisms for reductions in SMC number within lesions.
Aim 1 b will test the hypothesis that SMC-specific conditional KO of PDGF?R results in detrimental transitions in SMC phenotype including increased numbers of SMC-derived Lgals3+ foam cells (SMC-FC) and reduced numbers of SMC derived myofibroblasts (SMC-MF) within the fibrous cap.
Aim 2 will test the hypothesis that PDGF?R-signaling pathways confer atheroprotective effects within advanced atherosclerotic lesions at least in part through inducing favorable changes in SMC phenotype. Studies will test how SMC-specific or global genetic or pharmacologic inhibition (Aims 2a-2c) or augmentation (infusion of rPDGF- DD, Aim 2d) of PDGF?R signaling in Western diet fed ApoE-/- mice with advanced atherosclerotic lesions impacts overall lesion pathogenesis, indices of plaque stability, SMC phenotypic transitions, and the incidence of plaque rupture. Results may lead to development of novel therapeutic approaches for reducing late stage clinical complications of atherosclerosis by inducing SMC to undergo beneficial changes in phenotype-function that promote formation of a thicker and mechanically more stable fibrous cap, thus reducing the probability of plaque rupture and a possible MI or stroke.

Public Health Relevance

/Relevance: Atherosclerosis is a progressive disease that is a leading cause of death in the world. Remarkably, despite decades of research, little is known about late stage lesion development and mechanisms that result in the rupture of advanced atherosclerotic lesions leading to catastrophic thrombotic events including a heart attack (i.e. myocardial infarction) or a stroke. Drugs for reducing the probability of plaque rupture have largely focused on lipid lowering compounds and anti-inflammatory agents which thus far have only modestly reduced event rates or had no effect. The long term goal of studies in this proposal is to develop a completely novel approach for reducing the late stage clinical complications of atherosclerosis by inducing vascular smooth muscle cells (SMC) to undergo favorable changes in phenotype-function that promote formation of a thick mechanically stable fibrous cap (i.e. analogous to a patch on a tire) on advanced atherosclerotic lesions, thereby reducing the probability of them rupturing and setting off a possible heart attack or stroke.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL132904-03
Application #
9671443
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Olive, Michelle
Project Start
2017-04-01
Project End
2021-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Virginia
Department
Physiology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Gomez, Delphine; Baylis, Richard A; Durgin, Brittany G et al. (2018) Interleukin-1? has atheroprotective effects in advanced atherosclerotic lesions of mice. Nat Med 24:1418-1429
Durgin, Brittany G; Cherepanova, Olga A; Gomez, Delphine et al. (2017) Smooth muscle cell-specific deletion of Col15a1 unexpectedly leads to impaired development of advanced atherosclerotic lesions. Am J Physiol Heart Circ Physiol 312:H943-H958
Baylis, Richard A; Gomez, Delphine; Owens, Gary K (2017) Shifting the Focus of Preclinical, Murine Atherosclerosis Studies From Prevention to Late-Stage Intervention. Circ Res 120:775-777
Baylis, Richard A; Gomez, Delphine; Mallat, Ziad et al. (2017) The CANTOS Trial: One Important Step for Clinical Cardiology but a Giant Leap for Vascular Biology. Arterioscler Thromb Vasc Biol 37:e174-e177
DiRenzo, Daniel; Owens, Gary K; Leeper, Nicholas J (2017) ""Attack of the Clones"": Commonalities Between Cancer and Atherosclerosis. Circ Res 120:624-626
Gomez, Delphine; Owens, Gary K (2016) Reconciling Smooth Muscle Cell Oligoclonality and Proliferative Capacity in Experimental Atherosclerosis. Circ Res 119:1262-1264