About

Gary K. Owens is the Robert M. Berne Professor of Cardiovascular Research in the Department of Molecular Physiology and Biological Physics at the University of Virginia. His educational background includes a BS in Animal Science, an MS in Biology and Physiology, and a PhD in Biology and Physiology, all from Pennsylvania State University. He completed a postdoctoral fellowship in Pathology at the University of Washington, Seattle. His research focuses on the identification of factors and mechanisms that regulate the stability of late-stage atherosclerotic lesions and the probability of thromboembolic events such as heart attacks or strokes. Owens's work challenges existing dogma by demonstrating that smooth muscle cells (SMC) play a much greater role in lesion pathogenesis than previously understood. His studies have shown that SMC-derived cells are more prevalent in advanced lesions than earlier estimates suggested and that SMC can have both beneficial and detrimental effects depending on their phenotypic and functional transitions. His research employs lineage tracing, gene knockout models, RNA sequencing, and chromatin immunoprecipitation to explore how SMC phenotypic transitions influence lesion stability. Additionally, Owens investigates how mutations or gene polymorphisms linked to increased cardiovascular disease may promote detrimental SMC changes. His recent work extends to studying the role of SMC and pericyte phenotypic transitions in microvascular disease associated with Type II diabetes and metabolic disease, as well as in tumor cell growth and metastasis. His collaborative research with NIH has shown that factors secreted by highly metastatic tumor cells can induce Klf4-dependent reprogramming of SMC and pericytes, facilitating tumor invasion and survival. His findings indicate that targeting these phenotypic transitions could be critical for developing therapeutic strategies to promote plaque stability and combat metastasis.

Research topics

• Cell biology
• Medicine
• Biology
• Pathology
• Genetics
• Biochemistry
• Neuroscience
• Cancer research
• Immunology
• Endocrinology

Selected publications

• Dual Lineage Tracing Identifies Cellular Mechanisms Underlying Radiation-Associated Changes in Atherosclerotic Lesion Composition

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-15

  articleOpen accessSenior authorCorresponding

  Abstract Background Phenotypic plasticity of smooth muscle cells (SMCs) and endothelial cells (ECs) contributes to atherosclerotic plaque composition and stability, yet how shifts in one population influence the contribution and function of the other under conditions of vascular stress, such as irradiation, is poorly understood. A major limitation has been the inability to simultaneously fate-map both cell types within the same lesion, with most studies mapping one lineage while inferring the other using unreliable dynamically changing marker genes, risking false-positive and false-negative assignment. Methods We generated dual lineage-tracing Apoe -deficient mice, enabling simultaneous fate mapping of SMCs and ECs. This model was used to extend prior findings from single lineage-tracing models demonstrating irradiation-induced loss of SMC lesion investment and expansion of EC-derived cells. Dual lineage-tracing mice were subjected to irradiation and bone marrow transplantation, followed by Western diet feeding to induce atherosclerosis. Lineage tracing, immunostaining and scRNA-seq analysis were used to define coordinated SMC and EC responses and identify changes relevant to plaque instability. Results Dual lineage tracing specifically and simultaneously labeled SMC- and EC-derived cells in healthy and atherosclerotic vessels. Irradiation induced divergent responses: SMC-derived cells failed to invest in lesions and upregulated stress-activated inflammatory genes, whereas EC-derived cells expanded and upregulated SMC-associated genes. However, EC-derived cells within lesions failed to induce extracellular matrix genes, and lesions from irradiated mice exhibited reduced collagen content and fewer ACTA2 + cells within the fibrous cap, consistent with reduced plaque stability. Conclusions Dual lineage-tracing of SMCs and ECs demonstrated that irradiation-induced loss of lesional SMC and expansion of EC-derived ACTA2 + cells are not artifacts of false lineage assignment. By resolving SMC and EC fate within the same lesion, we identify irradiation-induced cell dynamics including stress-activated inflammatory reprogramming of SMCs, EC phenotypic modulation, impaired extracellular matrix organization, and reduced ACTA2⁺ fibrous cap cellularity that may contribute to radiotherapy-associated increased atherosclerotic cardiovascular disease risk. Clinical Perspective What Is New? We developed a dual lineage-tracing mouse model that enables simultaneous fate mapping of smooth muscle cells and endothelial cells within the same atherosclerotic lesion. This model reveals coordinated arterial cell wall responses to vascular injury that cannot be resolved using single lineage-tracing approaches. Extending prior observations, we show that irradiation-induced inflammatory reprogramming of smooth muscle cells and endothelial-to-mesenchymal transition of endothelial cells towards a smooth muscle cell-like state are associated with reduced total lesion collagen content and decreased overall ACTA2 + fibrous cap cellularity. This dual lineage-tracing mouse establishes a broadly applicable model for investigating arterial wall cell dynamics across diverse vascular disease states. What Are the Clinical Implications? Cancer therapies involving radiotherapy are associated with increased long-term risk of atherosclerotic cardiovascular disease. Our findings identify a potential cellular mechanism underlying this risk, in which irradiation-induced smooth muscle cell loss is not functionally compensated by endothelial-to-mesenchymal transition toward a SMC-like state. This dual lineage-tracing model provides a tool to evaluate how cancer therapies and other vascular stressors may alter arterial wall cell fate and indices of plaque stability in atherosclerosis and other vascular diseases.

  PublisherOA PDFDOI

• Endothelial-to-mesenchymal transition gene signature derived from single-cell transcriptomics of human atherosclerotic tissue associates with stable plaque histological characteristics

  Vascular Pharmacology · 2025-05-01 · 4 citations

  articleOpen access
  PublisherOA PDFDOI

• Glucocorticoids Disrupt Smooth Muscle Cell-Mediated Plaque Stabilization via Glucocorticoid Receptor-Dependent Inhibition of PDGF/TGFB Signaling

  Free Radical Biology and Medicine · 2025-10-30

  articleSenior author
  PublisherDOI

• Ponatinib, But Not the New Abl-Kinase Inhibitor Asciminib, Activates Platelets, Leukocytes, and Endothelial Cell TNF Signaling to Induce Atherosclerotic Plaque Inflammation, Myocardial Infarction, and Stroke

  Circulation · 2025-08-05 · 9 citations

  articleOpen access

  BACKGROUND: Imatinib, the first Abl-tyrosine kinase inhibitor (TKI), improved leukemia outcomes without cardiovascular side effects. Newer agents, including ponatinib, addressed imatinib resistance, improving cancer remission, but substantially increased arterial thrombotic events, including myocardial infarction (MI) and stroke. The mechanism behind ponatinib-induced thrombosis and the cardiovascular effect of asciminib, a newly approved Abl-TKI, remain unknown. METHODS: The effect of clinically relevant plasma concentrations of imatinib, ponatinib, and asciminib were compared with vehicle in vivo using SR-BI-mut/LDLR-knockout (KO) mice to assess spontaneous MI and stroke risk. The mechanism was interrogated in C57BL/6J mice, assessing leukocyte trafficking and thromboinflammation by intravital microscopy and flow cytometry, respectively, and in ApoE-KO mice, assessing plaque phenotype by flow cytometry and histology. In vitro effects on human umbilical vein endothelial cells (ECs) and human coronary artery ECs were determined by flow cytometry, PCR, and immunoblotting. The role of TNF (tumor necrosis factor) signaling was evaluated by pharmacological inhibition and small interfering RNA knockdown. RESULTS: In SR-BI-mut/LDLR-KO mice, ponatinib significantly accelerated death from MI and stroke compared with vehicle, imatinib, and asciminib. In human ECs, only ponatinib increased expression of TNF receptors (TNFRs) and adhesion molecules (P-selectin, ICAM1 [intercellular adhesion molecule 1], and VCAM1 [vascular cell adhesion molecule 1]). Ponatinib rapidly induced TNFR2 membrane trafficking and TNF signaling in human umbilical vein ECs. TNFR inhibition or TNFR2 knockdown prevented ponatinib induction of EC adhesion molecules. In vivo, ponatinib increased mesenteric vessel adhesion molecules, leukocyte rolling and adhesion to vessels, leukocyte and platelet activation, and platelet-leukocyte aggregates. In ApoE-KO mice, ponatinib increased plaque necrotic core and inflammation, consistent with a rupture-prone phenotype. Asciminib-treated mice developed none of these in vitro or in vivo toxicities. In C57BL/6J mice, TNFR inhibition blocked ponatinib-induced mesenteric adhesion molecule expression and leukocyte trafficking, but not platelet-leukocyte aggregation. TNFR blockade prevented ponatinib-induced plaque inflammation in ApoE-KO mice and MI and stroke in SR-BI-mut/LDLR-KO mice. CONCLUSIONS: Ponatinib, a potent anticancer therapy, activates ECs, platelets, and leukocytes, driving plaque inflammation and death from MI and stroke in mice, mirroring clinical cardiotoxicities in patients with cancer. Asciminib did not induce these effects, suggesting it might be a safer option for imatinib-resistant patients with cancer. Inhibition of TNFR-mediated endothelial activation is sufficient to prevent ponatinib-induced major adverse cardiovascular events.

  PublisherOA PDFDOI

• Ethnic Museums: Shifting Colonial Paradigms Toward Indigenized Alternatives

  Journal of the Southwest · 2025-03-01

  articleOpen accessSenior author

  The purpose of this article is to share common Indigenization challenges sampled from emergent O'odham museum experiences in southern Arizona.We discuss what these experiences may mean for the development of new protocols for Native museums in general and the relationship of evolving paradigms with conventional museum practices in particular.The article provides an update on the development of professional practices from the "shop floors" of southern Arizona's O'odham museums.We intend to bring awareness to what an originally Euro-centric museum idea set out to do and where Indigenous innovation is capable of making it go.The "database" resource for this paper is the authors' experience working in two (out of four) O'odham community museums, which we document with the aim of contributing to the formation of locally situated, stable

  PublisherOA PDFDOI

• Role of Diverse Smooth Muscle Cell Phenotypic Transitions in Atherosclerosis Development and Late-Stage Pathogenesis

  Annual Review of Physiology · 2025-11-04 · 3 citations

  articleOpen accessSenior author

  Major adverse cardiovascular events resulting from atherosclerotic plaque instability account for a plurality of deaths worldwide despite the use of highly effective lipid-lowering therapies. Over the last three decades, the role of inflammation in atherogenesis has been tested extensively. Although preclinical studies demonstrate a clear role for inflammation in atherogenesis, clinical studies using global anti-inflammatory therapies have not been as successful as hoped, encouraging the search for new therapeutic strategies. Thanks to the advent of cell-specific lineage tracing, we have begun to appreciate the multifaceted role of smooth muscle cell phenotypic switching in modulating plaque stability. Here, we review the mechanisms controlling smooth muscle cell phenotypic switching during early and late-stage pathogenesis, which may inspire future therapies to stabilize plaques.

  PublisherDOI

• Endothelial-to-Mesenchymal Transition Gene Signature Derived from Single-Cell Transcriptomics of Human Atherosclerotic Tissue Associates with Stable Plaque Histological Characteristics

  SSRN Electronic Journal · 2025-01-01

  preprintOpen access
  PublisherDOI

• Altered smooth muscle cell phenotypic switching in atherogenesis and -progression in a murine model of chemically induced colitis

  Atherosclerosis · 2024-08-01

  articleOpen access
  PublisherOA PDFDOI

• Growth Response of Aortic Smooth Muscle Cells in Hypertension

  2024-10-18 · 3 citations

  book-chapter1st authorCorresponding

  There is considerable interest in the cellular mechanisms responsible for the accelerated smooth muscle growth in arteries from hypertensive patients 1 and animals. 2,3 This interest derives from suggestions that (1) the accelerated smooth muscle growth associated with hypertension contributes to atherogenesis 4 —a disease in which intimal proliferation of smooth muscle cells is known to play a fundamental role 5,6 and (2) that medial smooth muscle hypertrophy in resistance vessels may play a role in the etiology of hypertension. 7 In this chapter I will: Review studies showing that the growth response of aortic smooth muscle cells is quite variable depending on the model of hypertension, with cellular hypertrophy and hyperploidy (i.e., enlargement of existing cells with DNA endoreplication) predominating in some cases and cellular hyperplasia (i.e., increased cell number) in others Discuss the possible mechanisms responsible for hypertrophic vs. hyperplastic growth of smooth muscle cells and the possible implications of these two types of cellular growth with regard to cell structure, function, and growth control processes as related to atherosclerosis and hypertension Consider the possible relevance of observations in large vessels to alterations in smooth muscle growth in resistance vessels of hypertensive animals and the possible role of this growth in the etiology of hypertension Discuss what I feel are the critical questions and future directions for research in this area

  PublisherDOI

• Treatment of advanced atherosclerotic mice with ABT-263 reduced indices of plaque stability and increased mortality

  JCI Insight · 2024-01-22 · 24 citations

  articleOpen accessSenior author

  The use of senolytic agents to remove senescent cells from atherosclerotic lesions is controversial. A common limitation of previous studies is the failure to rigorously define the effects of senolytic agent ABT-263 (Navitoclax) on smooth muscle cells (SMC) despite studies claiming that these cells are the major source of senescent cells. Moreover, there are no studies on the effect of ABT-263 on endothelial cells (EC), which - along with SMC - comprise 90% of α-smooth muscle actin+ (α-SMA+) myofibroblast-like cells in the protective fibrous cap. Here we tested the hypothesis that treatment of advanced atherosclerotic mice with ABT-263 will reduce lesion size and increase plaque stability. SMC (Myh11-CreERT2-eYFP) and EC (Cdh5-CreERT2-eYFP) lineage tracing Apoe-/- mice were fed a western diet (WD) for 18 weeks, followed by ABT-263 at 100 mg/kg/bw for 6 weeks or 50 mg/kg/bw for 9 weeks. ABT-263 treatment did not change lesion size or lumen area of the brachiocephalic artery (BCA). However, ABT-263 treatment reduced SMC by 90% and increased EC contributions to lesions via EC-to-mesenchymal transition (EndoMT) by 60%. ABT-263 treatment also reduced α-SMA+ fibrous cap thickness by 60% and was associated with a > 50% mortality rate. Taken together, ABT-263 treatment of WD-fed Apoe-/- mice with advanced lesions resulted in multiple detrimental changes, including reduced indices of stability and increased mortality.

  PublisherDOI

Recent grants

• NIH Grant R21HL071976

  NIH · $666k · 2006

• Oct4 and Klf4 regulate microvascular SMC-pericyte plasticity, angiogenesis, and metabolic dysfunction

  NIH · $3.1M · 2017–2022

• Defining SMC phenotypes critical in late stage atherosclerosis pathogenesis

  NIH · $3.0M · 2018–2022

• NIH Grant R01HL038854

  NIH · $6.3M · 2011

• NIH Grant R01HL057353

  NIH · $3.5M · 2017

Frequent coauthors

• Delphine Gomez

  University of Pittsburgh Medical Center

  60 shared

• Tadashi Yoshida

  57 shared

• Robert M. Starke

  Neurological Surgery

  51 shared

• Aaron S. Dumont

  Neurological Surgery

  49 shared

• Nohra Chalouhi

  University of Florida

  44 shared

• David Hasan

  44 shared

• Pascal Jabbour

  Jefferson University Hospitals

  43 shared

• Qiong Gan

  The University of Texas MD Anderson Cancer Center

  42 shared

Education

• Post-doctoral Fellowship in Cardiovascular Pathology, Pathology

  University of Washington

  1982

• BS, MS, PhD, Biology

  Pennsylvania State University

  1979