About

Brant Isakson is a Professor of Molecular Physiology and Biological Physics at the University of Virginia School of Medicine. His research focuses on translating discoveries in the microcirculation into tangible benefits for patients. The microcirculation, consisting of the smallest arteries and veins, plays a crucial role in modulating blood pressure, delivering oxygen to tissues, and regulating inflammatory responses. Isakson's lab has made significant contributions by developing genetically modified mouse models, patented products, and research disclosures that explore how altering specific proteins in blood vessels can impact health outcomes. His work has demonstrated that manipulating particular proteins in the microvasculature can drastically lower blood pressure or reduce inflammation and damage caused by strokes or heart attacks. The lab's ongoing efforts include recruiting human volunteers through an IRB to further test these findings and develop potential treatment modalities, emphasizing the translational aspect of his research.

Research topics

• Medicine
• Biology
• Internal medicine
• Cell biology
• Endocrinology
• Chemistry
• Biochemistry
• Neuroscience
• Artificial Intelligence
• Computer Science
• Pathology
• Pharmacology
• Cardiology
• Anatomy
• Materials science
• Evolutionary biology
• Molecular biology
• Immunology
• Bioinformatics
• Computational biology

Selected publications

• Guidelines for evaluating endothelial function in vascular tissue

  American Journal of Physiology-Heart and Circulatory Physiology · 2026-03-09

  articleOpen access

  The endothelium plays a central role in maintaining vascular homeostasis by orchestrating vascular tone, inflammation, healing, permeability, and thrombosis. Assessing endothelial function in vascular tissue is essential for understanding the cellular and molecular mechanisms underlying cardiovascular physiology and pathology. Traditional approaches, such as wire and pressure myography, have been instrumental in defining endothelium-dependent responses and identifying key pharmacological targets. However, the complexity and heterogeneity of endothelial cells across vascular beds and their dynamic phenotypic changes in health and disease necessitate the incorporation of new investigative strategies. Emerging methodologies, including bulk and single-cell transcriptomics, proteomics, and advanced imaging, now provide unprecedented insights into endothelial cell diversity and function. A team of leading experts in the field, who collectively reached a consensus on the most widely used techniques to evaluate endothelial function, developed these guidelines. The document establishes best practices for assessing endothelial function, from endothelial cell cultures to isolated vascular tissues, integrating conventional functional assays with modern molecular approaches. By fostering methodological consistency and embracing innovation, our goal is to enhance rigor, reproducibility, understanding, and discovery in endothelial biology.

  PublisherOA PDFDOI

• A single dose of i.v. iron induces cardiac ferroptosis in murine cardiometabolic heart failure

  JCI Insight · 2026-02-26

  articleOpen access
  PublisherOA PDFDOI

• Injury-induced connexin 43 expression regulates endothelial wound healing

  American Journal of Physiology-Heart and Circulatory Physiology · 2025-10-08 · 1 citations

  articleOpen access

  These findings demonstrate for the first time that mechanical injury to large artery endothelium induces the expression of gap junction protein Cx43. This upregulation improves the migratory and proliferative capacity of endothelial cells at the wound edge, facilitating timely wound closure. This phenomenon is dependent on appropriate gap junction function and turnover.

  PublisherDOI

• Multimodal analysis identifies pericyte-centered signaling programs altered by sex and brain region in Alzheimer’s Disease

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-09

  preprintOpen access

  Abstract Pericytes are critical components of the neurovascular unit (NVU), regulating endothelial cell (EC) stability, blood-brain barrier (BBB) integrity, and neuroimmune signaling. However, their role in Alzheimer’s Disease (AD), particularly in the context of sex differences and brain region specificity, remains poorly defined. Here, we use single-nucleus RNA sequencing (snRNA-seq) to characterize transcriptional and intercellular signaling changes in pericytes across the middle temporal gyrus (MTG) and dorsolateral prefrontal cortex (DLPFC) of the same AD and non-AD donors, stratified by sex. Using LIANA and Tensor-cell2cell, we identify latent communication programs altered in female AD donors, including a pericyte-EC signaling pattern that activates TGFβ via extracellular matrix ligands and is upregulated in the MTG but not the DLPFC. A second communication pattern, downregulated in female AD donors, reveals impaired estrogen pathway signaling through ligand-receptor interactions between pericytes and astrocytes. Supporting this, we observe reduced expression of pericyte-derived neuroligins and increased pericyte-astrocyte separation in a spatial transcriptomic subset. Additionally, we identify a microglia-to-pericyte signaling program conserved across brain regions, enriched for inflammatory pathways including hypoxia and p53, and elevated in both male and female AD donors with regional specificity. This result contrasts with the more sex-and region-specific pericyte signaling programs and suggests parallel mechanisms of NVU disruption between brain regions in AD. Our findings reveal brain region-specific and sex-specific pericyte signaling changes in AD and implicate vascular-, immune-, and synapse-associated pathways in NVU dysfunction. Altogether, the data suggest pericyte-driven communication as a mechanistic contributor to female-biased vulnerability in AD and support the need for sex-aware and region-specific approaches in neurodegeneration research.

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• <scp>AP</scp> ‐1 Is an Initial Convergent Transcriptional Response in Lymphatic Endothelium to <scp>VEGF</scp> ‐C or <scp>TNFα</scp>

  Microcirculation · 2025-11-01

  articleOpen accessSenior author

  OBJECTIVE: The lymphatic vasculature plays a central role in resolving inflammation by draining interstitial fluid, immune cells, and inflammatory mediators. While vascular endothelial growth factor C (VEGF-C) is a well-established driver of lymphangiogenesis, the effects of chronic pro-inflammatory cytokines on lymphatic remodeling remain incompletely defined. METHODS: Here, we investigated how tumor necrosis factor alpha (TNFα) compares with VEGF-C in regulating lymphatic endothelial structure and function using human dermal lymphatic endothelial cells (HDLECs). RESULTS: In tube formation and spheroid sprouting assays, both VEGF-C and TNFα supported early lymphangiogenic events, promoting robust sprouting and network development within 24 h. However, when pre-formed microvascular networks were challenged, prolonged TNFα exposure triggered progressive destabilization, characterized by tube fragmentation, reduced proliferation, and impaired metabolic activity, whereas VEGF-C preserved network stability. Mechanistically, both VEGF-C and TNFα induced rapid phosphorylation of p38 MAPK and upregulation of Activator Protein-1 (AP-1) transcription factor subunits within 30 min, suggesting a convergent early transcriptional response. Bulk RNA-sequencing confirmed shared induction of AP-1 family genes (FOS, JUN, ATF), highlighting AP-1 as a candidate regulator of the transition between adaptive and maladaptive outcomes. We propose that transient AP-1 activation promotes pro-lymphangiogenic programs, while sustained TNFα signaling redirects AP-1 activity toward stress, growth arrest, and apoptosis, leading to lymphatic regression. CONCLUSION: These findings identify TNFα as a temporally bifunctional regulator of lymphatic endothelial fate.

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• Pannexins in the vasculature

  American Journal of Physiology-Heart and Circulatory Physiology · 2025-10-06 · 2 citations

  reviewOpen accessSenior authorCorresponding

  Pannexins (PANX1, PANX2, PANX3) are a family of large-pore, ion and metabolite channels present throughout the blood and lymphatic vascular networks. PANX1 has near-ubiquitous expression in the cardiovascular system and is the most highly studied pannexin in both homeostatic and disease conditions. In smooth muscle, endothelium, and blood cells, PANX1 acts at the cell surface as an ATP efflux channel to drive many vascular processes such as vasoconstriction, blood pressure, endothelial barrier function, platelet aggregation, and acute hypoxic responses. Conversely, PANX2 and PANX3 are understudied and exhibit a more intracellular localization pattern, with endothelial PANX3 modulating blood pressure through channel-independent mechanisms. In this review, we discuss the cellular localization and function of pannexins throughout the cardiovascular system, including resistance arteries, veins, lymphatics, large vessels, erythrocytes, platelets, pericytes, hearts, and lungs, as well as how this cellular activity corresponds to vascular physiology at the organism level. We also discuss the contribution of pannexins to the development and progression of various cardiovascular diseases, such as hypertension, edema, sepsis, atherosclerosis, aortic aneurysms, myocardial infarction, ischemia reperfusion, and thrombosis. In most cardiovascular diseases, PANX1 exacerbates disease development and progression, as evidenced by PANX1 channel blockade or genetic deletion in murine models improving disease outcomes, whereas the beneficial action of PANX3 in healthy vessels seems to be lost in conditions such as hypertension. With the prevalence of cardiovascular diseases and the associated burden on patients and healthcare systems, pannexin-based therapeutics may represent a novel alternative or combinatorial strategy for the treatment of many vascular conditions.

  PublisherDOI

• Elastin Regulation of Vasoreactivity in Resistance Arteries

  Hypertension · 2025-10-01

  articleOpen accessSenior author

  BACKGROUND: Endothelial cells (ECs) are the primary producers of elastin in the internal elastic lamina (IEL) of resistance arteries. These arteries have distinct gaps in their IEL where ECs facilitate heterocellular communication with smooth muscle in a signaling microdomain termed the myoendothelial junction. However, the contribution of the IEL to vasodilation and blood pressure in resistance arteries is not well understood. METHODS: An endothelial-specific elastin knockout mouse (EC-specific Eln fl/fl /Cre + ) was used to alter the IEL and myoendothelial junctions. Myoendothelial junction resident proteins were localized by en face, pressure myography assessed the effect of elastin depletion on vessel dilation, and blood pressure was measured using radiotelemetry. RESULTS: Using single-cell RNA-sequencing, we found Eln mRNA enriched in arterial endothelium. In EC-specific Eln fl/fl /Cre + mice, the localization of the myoendothelial junction resident protein Hbα (α hemoglobin) becomes diffuse and disorganized. Normally, Hbα regulates eNOS (endothelial nitric oxide synthase) by sequestering NO, promoting endothelial-derived hyperpolarization as the predominant vasodilation mechanism. However, in EC-specific Eln fl/fl /Cre + mice, Hbα expression and interaction with eNOS are significantly reduced, corresponding to increased NO signaling via acetylcholine dilation. Intact arteries also exhibit decreased smooth muscle contractility with the diminished IEL. These vascular deficiencies suggested a hypotensive phenotype, but EC-specific Eln fl/fl /Cre + mice’s blood pressure was not different from controls. CONCLUSIONS: Our findings suggest that elastin deficiency in resistance arteries alters their vasoreactive properties, resulting in poor contraction and dilation. Furthermore, the absence of the holes in the IEL mislocalizes Hbα and eNOS in resistance arteries, switching the vasodilatory mechanism from endothelial-derived hyperpolarization to NO signaling, mimicking larger conduit arteries.

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• Nitrosation of CD36 Regulates Endothelial Function and Serum Lipids

  Arteriosclerosis Thrombosis and Vascular Biology · 2025-04-17 · 5 citations

  articleSenior author

  BACKGROUND: During obesity, endothelial cells (ECs) become lipid laden, leading to endothelial dysfunction. We tested posttranslational modification on cluster of differentiation 36 (CD36) that may regulate EC lipid accumulation. METHODS: We used an EC-specific Cav1 (caveolin-1) knockout mouse, nitrosation and palmitoylation assays, and whole animal Nγ-nitro-l-arginine methyl ester administration to examine blood lipids. RESULTS: EC-specific Cav1 knockout male mice are hyperlipidemic regardless of diet but retain endothelial cell function. We found these mice have significantly increased NO in response to the lack of Cav1, and the presence or absence of NO toggled inversely EC lipid content and plasma lipid in mice. The NO nitrosated the fatty acid translocase CD36 at the same cysteines that are palmitoylated on CD36. The nitrosation of CD36 prevented its trafficking to the plasma membrane and decreased lipid accumulation. The physiological effect of this mechanism was a reliance on NO for endothelial function and not dilation. CONCLUSIONS: This work suggests that CD36 nitrosation occurs as a protective mechanism to prevent EC lipotoxicity.

  PublisherDOI

• Pannexin channels in the kidney

  American Journal of Physiology-Renal Physiology · 2025-10-03

  reviewOpen accessSenior authorCorresponding

  Renal dysfunction leads to critical health conditions, including acute kidney injury (AKI) and chronic kidney disease (CKD), and is a driver of hypertension. Despite their global prevalence and impact, the pathophysiology for all kidney disease subtypes is incompletely understood; therefore, many patients progress to kidney failure, needing dialysis and transplantation. This review highlights the role of pannexins-a family of channel-forming glycoproteins-in renal physiology and pathophysiology. Compared with other organ systems such as the brain and cardiovascular system, relatively little is known about the function of pannexins in the kidney. However, recent findings indicate that pannexins may be potential therapeutic targets in the treatment of hypertension, AKI, and CKD, though further research is needed to fully understand their precise role in renal health and disease.

  PublisherDOI

• Adipose Tissue Expansion is Dependent on a Piezo2-Vegfr3 Signaling Axis that Regulates Lymphangiogenesis

  Physiology · 2025-05-01

  articleSenior author

  Obesity and impaired lymphangiogenesis are closely interrelated. One of the consequences of obesity is decreased density of lymphatic vessels, whereas not fully functional lymphatic vessels lead to the accumulation of lipids primary in adipose tissue. Adipose tissue is rich in both blood and lymphatic vessels, making it constantly under mechanical perturbation by blood and lymph flow. In this project we sought to understand how mechanical signals may mediate dynamic changes in adipose expansion. For this purpose, we have focused on Piezo channels which are mechanosensitive currents activated by shear stress, fluid flow and membrane tension, resulting in an intracellular influx of calcium. Our data of single cell RNA-seq analysis performed on adipose and mesenteric endothelium indicated that different Piezo channels have their own specialized localization within lymphatic endothelium. Piezo1 was a marker of lymphatic collecting duct endothelium, but Piezo2 was a marker of lymphatic capillary endothelium. In this project we initially focused on Piezo2 due to the high density of lymphatic capillaries in adipose tissue. Generated obesogenic Piezo2 fl/fl /Prox1-Cre ERT2+ mice were found to have significantly increased insulin tolerance, significantly increased weight and epigonadal fat pads. Importantly, there was no change in the water mass of the animals. Because decreased lymphangiogenesis correlates with adipose expansion, we hypothesize that Piezo2 may regulate lymphangiogenesis. In obesogenic Piezo2 fl/fl /Prox1-Cre ERT2+ mice, adipose lymphatics lost expression of Piezo2 and Flt4 (gene encoding main regulator of lymphangiogenesis – Vegfr3). This was also observed in humans, where higher BMI correlated with decreased expression of PIEZO2 and FLT4 in lymphatic capillaries of adipose tissue. To test our hypothesis, we used PIEZO2 siRNA on human dermal lymphatic endothelial cells (HDLECs) and demonstrated a significant reduction in FLT4 mRNA, with a regression analysis of PIEZO2 and FLT4 expression of r 2 =0.722. What is more, we haven’t observed a reduction of PIEZO2 mRNA after FLT4 siRNA knock-down in HDLECs. Treatment of lipids highly present in obesogenic diet led to decreased expression of PIEZO2 and FLT4 with unchanged expression level of PIEZO1, and decreased proliferation of HDLECs. Additionally, by Ki67 staining we shown that loss of PIEZO2 significantly decreased proliferation of HDLECs. Considering the Piezo2-dependent regulation of Flt4 expression, we proposed a potential model for their interaction with proximity ligation assay. Piezo2 dependent calcium pool in the cell's cytoplasm interacts with Calmodulin, which forms a ternary protein complex with Klf2 and the transcription factor Prox1 – regulator of Vegfr3 maintenance. To determine physiological implications of Piezo2 from lymphatic endothelial cells on lymphatic vessels density in adipose tissue light sheet analysis was performed. In conclusion, we propose a novel function of Piezo2 as a regulator of Flt4 expression that affects lymphangiogenesis in adipose to regulate expansion. Project is founded by public sources: NIH HL137112; NIH HL171997 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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Recent grants

• Purinergic Regulation of Veinous Endothelial Permeability

  NIH · $4.1M · 2018–2027

• NIH Grant F32HL079772

  NIH · $7k · 2005

• Mechanisms of Heterocellular Signaling at the Myoendothelial Junction

  NIH · $3.8M · 2008–2019

• Pannexin Channels In Vascular Physiology & Inflammation

  NIH · $48.1M · 2014–2025

• NIH Grant R21HL107963

  NIH · $414k · 2013

Frequent coauthors

• Marie Billaud

  Harvard University

  164 shared

• Scott R. Johnstone

  Virginia Tech

  146 shared

• Adam C. Straub

  University of Pittsburgh

  145 shared

• Angela K. Best

  University of Virginia

  129 shared

• Miranda E. Good

  Tufts Medical Center

  89 shared

• Alexander W. Lohman

  University of Calgary

  78 shared

• Leon J. DeLalio

  University of Pittsburgh

  71 shared

• Kodi S. Ravichandran

  Ghent University

  71 shared