Owens, Gary K.

Gary Owens

Gary K. Owens

Primary Appointment

Robert M. Beirne Professor of Cardiovascular Research, Molecular Physiology and Biological Physics

Education

  • BS, Animal Science, Pennsylvania State University
  • MS, Biology and Physiology, Pennsylvania State University
  • PhD, Biology and Physiology, Pennsylvania State University
  • Postdoc, Pathology, University of Washington, Seattle

Contact Information

PO Box 800736
Room 1322 MR5
Telephone: 434-924-2652
Email: gko@virginia.edu
Website: https://www.cvrc.virginia.edu/Owens/

Research Interests

Identification of Factors and Mechanisms that Regulate the Stability of Late Stage Atherosclerotic Lesions and the Probability of Thromboembolic Events Including a Heart Attack or Stroke

Research Description

Identification of Factors and Mechanisms that Regulate the Stability of Late Stage Atherosclerotic Lesions and the Probability of Thromboembolic Events Including a Heart Attack or Stroke Atherothrombosis, resulting from rupture or erosion of unstable atherosclerotic plaques, is the leading cause of death worldwide. However, the mechanisms that regulate the stability of late stage atherosclerotic lesions remain poorly understood. The general dogma based on extensive human histopathology studies is that: 1) plaque composition not size is a critical determinant of late stage lesion stability and the probability of rupture or erosion and a possible heart attack or stroke; 2) plaques containing a large necrotic core, a thin fibrous cap, and large numbers of CD68+ cells relative to Acta2+ cells [presumed to be macrophages (M?) and smooth muscle cells (SMC) respectively] are more prone to rupture or erosion; and 3) the primary role of the SMC is athero-protective by virtue of them being the primary cell type responsible for formation of a protective fibrous cap. However, several recent Nature Medicine studies1, 2 by our lab involving simultaneous SMC lineage tracing and SMC-specific knockout (KO) of the stem cell pluripotency genes Oct4 or Klf4, have provided compelling evidence challenging this dogma and showing that SMC play a much greater role in lesion pathogenesis than has been generally appreciated [see our recent review3]. For example, we showed that >80% of SMC-derived cells within advanced lesions of ApoE-/- mice fed a Western diet (WD) for 18 weeks lacked detectable expression of SMC markers such as Acta2 typically used to identify them meaning that previous studies in the field have grossly under-estimated the number of SMC-derived cells within advanced lesions. Moreover, >30% of cells previously identified as M? within advanced mouse brachiocephalic artery (BCA) lesions and human advanced coronary artery lesions were found to be of SMC not myeloid origin meaning that previous estimates of SMC/ M? ratios are highly inaccurate. Even more importantly, we found that SMC can play either a beneficial or detrimental role in lesion pathogenesis depending on the nature of their phenotypic/functional transitions. For example, Klf4-dependent transitions, including formation of SMC-derived M?-marker+ foam cells1 exacerbated lesion pathogenesis whereas Oct4-dependent transitions2 were atheroprotective including being critical for migration and investment of SMC into a protective fibrous cap. Indeed, remarkably, results of RNAseq and Oct4/Klf4 CHIPseq analyses of advanced brachiocephalic lesions from SMC Klf4 versus SMC Oct4 knockout mice showed virtually completely opposite genomic signatures. Taken together, results show that SMC play an absolutely critical, even dominant role, in late stage lesion pathogenesis in that conditional loss of a single gene in SMC can completely alter lesion pathogenesis [see our recent review3]. A major focus of our current studies is to identify factors, mechanisms, and potential therapeutic targets that can promote beneficial, and/or inhibit detrimental SMC phenotypic transitions within advanced lesions and thereby promote increased plaque stability. In addition, we are determining if mutations or gene polymorphisms that are linked to increased cardiovascular disease in humans may function, at least in part, by promoting detrimental changes in SMC phenotype and their associated functions. Finally, we have initiated additional studies investigating the potential role of SMC and pericyte phenotypic transitions in the pathogenesis of microvascular disease associated with Type II diabetes/metabolic disease, and in regulation of tumor cell growth and metastasis. The latter studies, which were published in Nature Medicine4 and done in collaboration with Dr. Kaplan?s lab at NIH, showed that highly metastatic tumor cells secrete factors that circulate in blood and induce Klf4-dependent reprogramming of SMC and pericytes within metastatic niches that make them permissive for tumor cell invasion and survival. Remarkably, we found that SMC-pericyte specific knockout of the stem cell pluripotency gene Klf4 dramatically reduced tumor metastasis by >70%. Reference List:
(1) Shankman LS, Gomez D, Cherepanova OA, Salmon M, Alencar GF, Haskins RM, Swiatlowska P, Newman AA, Greene ES, Straub AC, Isakson B, Randolph GJ, Owens GK. KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis. Nat Med 2015 May 18;21(6):628-37.
(2) Cherepanova OA, Gomez D, Shankman LS, Swiatlowska P, Williams J, Sarmento OF, Alencar GF, Hess DL, Bevard MH, Greene ES, Murgai M, Turner SD, Geng YJ, Bekiranov S, Connelly JJ, Tomilin A, Owens GK. Activation of the pluripotency factor OCT4 in smooth muscle cells is atheroprotective. Nat Med 2016 May 16;22(6):657-65.
(3) Bennett MR, Sinha S, Owens GK. Vascular Smooth Muscle Cells in Atherosclerosis. Circ Res 2016 February 19;118(4):692-702.
(4) Murgai M, Ju W, Eason M, Kline J, Beury DW, Kaczanowska S, Miettinen MM, Kruhlak M, Lei H, Shern JF, Cherepanova OA, Owens GK, Kaplan RN. KLF4-dependent perivascular cell plasticity mediates pre-metastatic niche formation and metastasis. Nat Med 2017 October;23(10):1176-90.

Selected Publications