Mark Renton’s journey from aspiring sports scientist in Australia to postdoctoral researcher at Virginia Tech’s Fralin Biomedical Research Institute underscores a broader shift in biomedical research: the convergence of exercise physiology and cellular biology. While he grew up dreaming of designing exercise regimens for elite athletes, an undergraduate course in exercise metabolism awakened Renton’s fascination with the cellular machinery of muscle. That curiosity ultimately led him to pursue a doctorate in cardiac biology, and more recently, to investigate how obesity undermines heart health at the microscopic level.
Now, Renton has been selected for a prestigious postdoctoral fellowship from the American Heart Association (AHA) to study coronary microvascular dysfunction—a subtle but important precursor of overt heart disease. With support from this award, he will elucidate how a specific membrane channel protein, pannexin-1, mediates the harmful effects of excess weight on coronary blood vessels. His work may pave the way for new interventions that preserve microvascular function not only in the heart but throughout the body.
Obesity and Coronary Microvascular Disease: The Hidden Threat
When most people think of heart disease, they envision clogged arteries, heart attacks, and bypass surgeries. Yet many cardiac problems begin long before a critical blockage appears. Coronary microvascular dysfunction involves abnormalities in the heart’s smallest blood vessels—capillaries and arterioles—that regulate myocardial perfusion. These tiny vessels are critical for matching blood flow to the oxygen demand of cardiac muscle. When they lose their ability to dilate and constrict appropriately, patients experience chest pain (angina), even when major coronary arteries remain unobstructed.
Obesity is a well-established risk factor for coronary microvascular disease. Excess adiposity triggers chronic, low-grade inflammation, insulin resistance, and dyslipidemia—all of which can impair endothelial function and smooth muscle responsiveness. The result is impaired vasodilation, increased vasoconstriction, and a propensity for vessel spasms that starve the myocardium of oxygen. Over time, these microvascular abnormalities can progress to ischemia, heart failure with preserved ejection fraction (HFpEF), and other serious cardiac conditions.
Despite the recognized link, the precise molecular pathways by which obesity disrupts microvascular homeostasis remain incompletely understood. Identifying those pathways is critical for developing preventive and therapeutic strategies—especially since microvascular dysfunction often precedes more dramatic occlusive disease. This is where Renton’s work on pannexin-1 enters the picture.
Pannexin-1: A Molecular Gatekeeper of Vascular Tone
Pannexin-1 is a plasma membrane channel expressed in various tissues, including vascular endothelial cells and smooth muscle. Structurally analogous to connexins, which form gap junctions between adjacent cells, pannexin-1 operates as a nonjunctional channel that allows the passage of ions and small signaling molecules, such as ATP, to the extracellular environment. By releasing ATP and other nucleotides, pannexin-1 channels modulate purinergic signaling—a critical pathway regulating vasodilation, inflammation, and platelet aggregation.
In the context of coronary microvasculature, pannexin-1 appears to facilitate appropriate endothelial and smooth muscle responses. Under normal conditions, shear stress and metabolic stimuli cause pannexin-1–mediated ATP release, which binds to purinergic receptors on endothelial cells (e.g., P2X and P2Y families). This triggers a cascade culminating in nitric oxide (NO) production and vascular relaxation. Simultaneously, pannexin-1 may also coordinate intercellular calcium waves via paracrine signals, ensuring synchronized vasodilatory responses across capillary networks. When pannexin-1 function is compromised—whether by genetic deletion, posttranslational modifications, or downregulation—the resulting impairment in purinergic and nitric oxide signaling leads to reduced vasodilatory capacity, endothelial dysfunction, and a predisposition to spasms.
The Johnstone Lab Discovery: Pannexin-1 and Obesity-Induced Dysfunction
Renton’s mentor, Dr. Scott Johnstone, directs the Center for Vascular and Heart Research within the Fralin Biomedical Research Institute at Virginia Tech Carilion (VTC). The Johnstone lab recently published pivotal findings demonstrating that the absence of pannexin-1 in murine coronary microvessels recapitulates many hallmarks of obesity-induced microvascular dysfunction. In conditional knock-out mice lacking endothelial pannexin-1, coronary arterioles exhibited blunted dilation in response to flow and metabolic cues, increased vasoconstriction, and heightened susceptibility to endothelin-1–mediated spasm. Notably, these phenotypes closely mirrored those observed in diet-induced obese mice that retained pannexin-1 expression, suggesting that obesity may suppress pannexin-1 expression or alter its functional properties.
“We observed that when pannexin-1 is removed, blood vessels in the heart lose their normal ability to expand and contract—exactly what we also see in obese animals,” explains Renton. “That raised the tantalizing question: Is obesity causing a loss of pannexin-1 expression, or is it modifying upstream signals that impair channel function? The AHA fellowship will allow us to answer that.”
Key Aims of the AHA-Funded Research
With funding from the AHA, Renton will focus on three interrelated objectives:
- Quantify Pannexin-1 Expression and Localization in Obese Versus Lean Models
• Employ lean and diet-induced obese mice to compare pannexin-1 mRNA and protein levels in coronary endothelial cells and smooth muscle cells.
• Use immunohistochemistry and confocal microscopy to determine whether obesity alters pannexin-1 subcellular localization (e.g., internalization versus plasma membrane retention).
• Analyze posttranslational modifications—such as phosphorylation or S-nitrosylation—that may influence channel gating or stability under obese conditions. - Determine Functional Consequences of Pannexin-1 Modulation in Obesity
• Perform ex vivo wire myography on isolated coronary arterioles from lean and obese mice to measure dose–response curves to vasodilators (e.g., acetylcholine, adenosine, flow- mediated dilation) and vasoconstrictors (e.g., endothelin-1).
• Evaluate whether pharmacological activation or inhibition of pannexin-1 (using specific peptides or small-molecule modulators) can rescue or worsen microvascular function in obese models.
• Conduct in vivo hemodynamic studies (e.g., pressure–diameter measurements via ultrasound or magnetic resonance imaging) to assess myocardial perfusion under rest and stress conditions. - Investigate Downstream Molecular Pathways: Purinergic Signaling and Nitric Oxide
• Quantify extracellular ATP release from isolated endothelial cells under shear stress in lean versus obese conditions, correlating ATP levels with pannexin-1 expression.
• Measure phosphorylation status of endothelial nitric oxide synthase (eNOS) and resultant NO production in response to pannexin-1 modulation.
• Evaluate the expression and activation of purinergic receptors (P2X4, P2Y6) that mediate ATP’s vasodilatory effects, as well as pathways leading to IL-1β production in response to pannexin-1–driven pyroptosis signals.
By addressing these aims, Renton’s project seeks to delineate whether obesity’s deleterious effects on coronary microvessels stem from reduced pannexin-1 expression, impaired channel gating, or downstream blockade of purinergic/NO signaling cascades. Understanding the precise mechanism is crucial for designing targeted interventions—whether by restoring pannexin-1 expression, enhancing its gating, or compensating via downstream agonists of purinergic receptors.
Clinical Relevance: Preventing Microvascular Ischemia in Obese Patients
Coronary microvascular dysfunction often manifests as angina with “normal” epicardial coronary arteries on angiography—a clinical entity termed microvascular angina or cardiac syndrome X. These patients endure debilitating chest pain, exercise intolerance, and reduced quality of life, yet their condition is often dismissed as non-cardiac in origin. In obese individuals—especially women—microvascular angina is strikingly prevalent and portends a higher risk of major adverse cardiovascular events, heart failure with preserved ejection fraction (HFpEF), and mortality.
Current therapeutic options for microvascular dysfunction are limited and largely empirical: calcium channel blockers, nitrates, and lifestyle modifications. None specifically target the underlying molecular derangements, such as impaired pannexin-1–mediated signaling. If Renton’s research confirms that obesity directly downregulates pannexin-1 or disrupts its function, novel therapies could be engineered to restore channel activity, preserve ATP release, and maintain endothelial NO production. Such interventions could forestall microvascular ischemia before irreversible myocardial damage occurs.
The Significance of Targeting Early-Stage Dysfunction
Extensive epidemiological data link obesity to accelerated atherosclerosis and plaque formation in large coronary arteries. However, microvascular dysfunction can ensue even in the absence of overt atherosclerotic lesions. By focusing on the microcirculation—where each capillary’s perfusion status is critical for matching myocardial oxygen demand—Renton’s work addresses a gap in early-stage diagnosis and prevention. Microvascular dysfunction can emerge years before macrovascular disease becomes clinically apparent, offering a window of opportunity for targeted interventions that might prevent progression to full-blown ischemic heart disease.
Obesity’s Systemic Impact: Beyond the Heart
Although Renton’s fellowship centers on coronary microvessels, its implications extend to other organ systems. Similar pannexin-1–dependent purinergic pathways regulate blood flow in the brain, kidneys, skeletal muscle, and adipose tissue. In the brain, microvascular dysfunction contributes to vascular cognitive impairment; in the kidneys, it underlies early diabetic nephropathy and chronic kidney disease. Therefore, deciphering how obesity alters pannexin-1 function could inform strategies to prevent or ameliorate a spectrum of obesity‐related conditions, from cerebrovascular disease to chronic kidney injury.
Collaborative Framework: Mentors and Multidisciplinary Support
Renton’s postdoctoral fellowship is anchored in a collaborative, multidisciplinary environment at the Fralin Biomedical Research Institute. In addition to Dr. Scott Johnstone, his primary mentor, Renton collaborates closely with Professor Steven Poelzing—an expert in cardiac electrophysiology and imaging—and Assistant Professor Jessica Pfleger, who specializes in vascular biology and molecular imaging. This trio ensures that Renton’s investigations span cellular assays, ex vivo functional studies, and in vivo physiological measurements, providing a comprehensive assessment of pannexin-1’s role in obesity.
• Dr. Scott Johnstone (Assistant Professor of Physiology and Biomedical Sciences) established the lab’s focus on coronary microvascular function. His prior publications characterized pannexin-1 knockout models and demonstrated their phenotypic parallels with obese animals. Under Johnstone’s guidance, Renton will leverage new transgenic mouse models—such as inducible, endothelial-specific pannexin-1 knockdown—to parse cell‐type–specific effects.
• Professor Steven Poelzing (Associate Professor of Physiology and Biomedical Sciences) has pioneered noninvasive imaging protocols to measure myocardial blood flow and ventricular function in small animals. His expertise in pressure–diameter myography and contrast‐enhanced ultrasound will be instrumental as Renton extends in vitro findings to live, anesthetized mouse preparations, quantifying real‐time changes in microvascular perfusion under stress.
• Assistant Professor Jessica Pfleger (Assistant Professor of Biomedical Sciences) brings advanced molecular imaging and fluorescence lifetime microscopy to the team. Her methods allow visualization of pannexin-1 localization in situ and measurement of intracellular calcium dynamics—key endpoints when evaluating channel gating.
A Timeline for Discovery: Milestones in the Fellowship Period
Renton’s AHA fellowship extends over two years, with the following projected milestones:
Year 1
– Establish lean and diet-induced obese mouse colonies, validate obesity phenotypes (e.g., body weight, insulin resistance).
– Optimize pannexin-1 expression assays (qPCR, Western blot, immunofluorescence) in coronary endothelial cells and smooth muscle cells isolated from mice.
– Complete initial ex vivo wire myography studies comparing vasoreactivity in lean versus obese vessels, with and without pharmacological pannexin-1 modulation.
– Submit preliminary abstracts to AHA Scientific Sessions and the International Microcirculation Society meeting.
Year 2
– Finalize in vivo myocardial perfusion imaging (e.g., contrast ultrasound, magnetic resonance imaging) under rest and dobutamine stress.
– Characterize downstream signaling: ATP release assays, eNOS phosphorylation status, and NO metabolite measurements in vessel lysates.
– Publish key manuscripts detailing: (1) obesity’s effect on pannexin-1 expression; (2) functional rescue of microvascular responses by pannexin-1 activators; (3) altered purinergic receptor profiles in obesity models.
– Develop a proof-of-concept small-molecule screen to identify candidate pannexin-1 modulators using cell‐based assays.
By the end of the fellowship, Renton aims to submit a detailed proposal for translational research, including early-phase testing of pannexin-1 modulators in other vascular beds (e.g., cerebral microvessels) and exploring collaborations with pharmaceutical partners.
Translational Potential: Toward Novel Therapeutics
No current medications specifically target pannexin-1 in clinical use. However, several research‐grade peptides and small molecules—such as carbenoxolone (a pannexin-1 inhibitor) and probenecid (a known channel modulator)—provide starting points. Renton’s work may reveal whether upregulating pannexin-1 expression or enhancing its gating can normalize coronary microvascular function in obese models. If successful, this approach could lead to:
– Biologic or peptide therapies that selectively augment pannexin-1 activity in endothelial cells.
– Small‐molecule drugs that stabilize pannexin-1 channels on the plasma membrane or block obesity‐induced inhibitory modifications (e.g., phosphorylation).
– Gene therapy vectors using adeno‐associated virus (AAV) to deliver functional pannexin-1 alleles to the microvasculature.
– Nutraceutical interventions—such as identified dietary components that preserve pannexin-1 function (e.g., omega-3 fatty acids known to modulate purinergic pathways).
Such innovations could transform the management of microvascular angina, HFpEF, and exercise intolerance in obese patients. Instead of merely addressing risk factors (e.g., weight loss, blood pressure control), therapies targeting pannexin-1 could directly rectify the cellular defect responsible for impaired microvascular perfusion.
Broader Implications: Pannexin-1 in Other Obesity-Related Conditions
Coronary microvascular dysfunction represents only one facet of obesity’s systemic impact. Analogous mechanisms may underlie early microvascular changes in the brain—contributing to vascular cognitive impairment—and in the kidneys—promoting glomerular hyperfiltration and progression to chronic kidney disease. If obesity reduces pannexin-1 expression or function in these tissues, similar corrective strategies could be applicable across multiple organ systems.
For example, in the cerebral microcirculation, pannexin-1–mediated ATP release influences endothelial and astrocytic signaling that regulates neurovascular coupling. Impaired pannexin-1 function may lead to decreased cerebral blood flow and subtle hypoperfusion, contributing to cognitive decline in obesity and type 2 diabetes. In renal microvessels, defective pannexin-1 channels may impede tubuloglomerular feedback and promote maladaptive hyperfiltration, fueling diabetic nephropathy. Thus, Renton’s heart‐centered research could catalyze new lines of inquiry into obesity’s effects on brain and kidney microvasculature, broadening therapeutic possibilities.
The Fellowship’s Role in Shaping Future Research Leadership
The American Heart Association’s postdoctoral fellowship not only provides financial support but also cultivates future scientific leaders in cardiovascular research. For Renton, the award signifies recognition of his potential to unravel fundamental mechanisms linking obesity to microvascular dysfunction. As he works under the guidance of leading vascular researchers, he is accumulating the skills and data necessary to launch his independent research trajectory.
Dr. Johnstone emphasizes Renton’s progress: “Mark is already a productive scientist who has contributed critical insights into how pannexin-1 shapes coronary microvascular function. This AHA award will enable him to complete the mechanistic puzzle and embark on a career dedicated to unmet needs in cardiovascular disease prevention. He’s well on his way to establishing a research group of his own.”
Scientific Community Reactions and Collaborative Opportunities
Within the broader cardiovascular research community, Renton’s project has generated excitement. Dr. Zayd Ibrahim, an obesity cardiology specialist at the University of California, San Francisco, comments: “Microvascular dysfunction in obese patients is an underappreciated contributor to heart failure with preserved ejection fraction. Understanding upstream regulators like pannexin-1 could revolutionize how we approach these patients—shifting from symptomatic treatment to mechanism-based prevention. Mark’s fellowship will accelerate discoveries in a highly translational area.”
Moreover, Dr. Angela Park, a nephrologist at Johns Hopkins University, notes potential cross-disciplinary collaborations: “Renton’s findings may have implications for diabetic kidney disease, where early microvascular changes drive progression. We look forward to partnering with him to explore pannexin-1’s role in renal capillary health and potentially co‐develop therapeutic strategies.”
Looking Ahead: The Path to Clinical Translation
While basic research often spans years, the translational potential of Renton’s pannexin-1 project is relatively clear. If his fellowship confirms that obesity universally impairs pannexin-1 expression or function, the next steps could involve:
• Screening existing pharmacological libraries for compounds that enhance pannexin-1 activity or prevent its degradation under obese conditions.
• Conducting early‐phase safety and pharmacokinetic studies of top candidate molecules in small animal models, followed by large‐animal studies for dosing and efficacy.
• Designing clinical trials in obese patients with microvascular angina or HFpEF to test whether pannexin-1–targeted therapies improve myocardial perfusion, reduce chest pain episodes, and enhance exercise tolerance.
Because pannexin-1 also participates in inflammatory signaling (e.g., NLRP3 inflammasome activation), careful attention to off-target or proinflammatory effects will be essential. Nonetheless, the specificity of microvascular dysfunction in obesity—absent major atherosclerosis—provides a well‐defined patient population likely to benefit from mechanism‐based interventions.
Conclusion: Toward a Future Where Genes Are Not Destiny
Mark Renton’s receipt of the American Heart Association postdoctoral fellowship represents more than personal achievement; it embodies a new era in cardiovascular research, one that harnesses genetic insights to shape personalized prevention. By decoding how obesity downregulates or disables a single channel protein—pannexin-1—Renton aims to intercept the cascade of events leading from adiposity to microvascular ischemia.
Ultimately, his work may alter the paradigm of heart disease management. Instead of reacting to advanced atherosclerosis or heart failure after symptoms appear, we may soon identify—and correct—subcellular dysfunctions before clinical disease manifests. For patients grappling with obesity, such advances could mean avoiding chronic chest pain, preventing heart failure, and preserving quality of life.
As Renton and his colleagues at the Fralin Biomedical Research Institute embark on this ambitious project, the cardiovascular community eagerly anticipates results that may reshape clinical practice. In a world where obesity rates continue to climb, unraveling the molecular interplay between fat and microvasculature is not merely academic—it is a critical step toward reducing the global burden of heart disease.
For now, Renton’s story—from an Australian football pitch to the frontiers of cardiac cellular biology—reminds us that the path to preventing heart disease often begins with a curious mind and a willingness to explore the smallest building blocks of life. As he studies pannexin-1 in the lab, his ultimate goal is clear: to ensure that obesity is no longer a guaranteed passage to heart failure, but rather a modifiable factor that can be neutralized at the molecular level.
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