A5045288982- Connexins and lens biology
- Nitric Oxide and Endothelin Effects
- Heme Oxygenase-1 and Carbon Monoxide
- Cardiovascular Disease and Adiposity
- Biochemical effects in animals
- Atherosclerosis and Cardiovascular Diseases
- Neuroscience of respiration and sleep
- Cardiovascular, Neuropeptides, and Oxidative Stress Research
- Heat shock proteins research
- Hemoglobin structure and function
- Endoplasmic Reticulum Stress and Disease
- Nicotinic Acetylcholine Receptors Study
- Hormonal Regulation and Hypertension
- Epigenetics and DNA Methylation
- Extracellular vesicles in disease
- Receptor Mechanisms and Signaling
- Renin-Angiotensin System Studies
- Biomarkers in Disease Mechanisms
- Cancer-related molecular mechanisms research
- Cancer-related gene regulation
- Thermoregulation and physiological responses
- Hearing, Cochlea, Tinnitus, Genetics
- RNA modifications and cancer
- Cellular transport and secretion
- Ion Channels and Receptors
Tufts Medical Center
2017-2025
University of Virginia
2015-2023
Cardiovascular Research Center
2015-2018
University of Virginia Health System
2018
Williams (United States)
2017
Carter Center
2017
La Trobe University
2017
William & Mary
2017
Dalian Medical University
2016
Washington University in St. Louis
2016
Current paradigms suggest that nitric oxide (NO) produced by endothelial cells (ECs) through synthase (eNOS) in the vessel wall is primary regulator of blood flow and pressure. However, red (RBCs) also carry a catalytically active eNOS, but its role controversial remains undefined. This study aimed to elucidate functional significance RBC eNOS compared with EC for vascular hemodynamics metabolism. We generated tissue-specific loss- gain-of-function models using cell-specific Cre-induced gene...
Rationale: Resistant hypertension is a major health concern with unknown cause. Spironolactone an effective antihypertensive drug, especially for patients resistant hypertension, and considered by the World Health Organization as essential medication. Although spironolactone can act at mineralocorticoid receptor (MR; NR3C2), there increasing evidence of MR-independent effects spironolactone. Objective: Here, we detail unexpected discovery that Panx1 (pannexin 1) channels could be relevant in...
Ischemia-reperfusion (I/R) injury (IRI), which involves inflammation, vascular permeability, and edema, remains a major challenge after lung transplantation. Pannexin-1 (Panx1) channels modulate cellular ATP release during inflammation. This study tests the hypothesis that endothelial Panx1 is key mediator of inflammation edema I/R IRI can be blocked by antagonism. A murine hilar ligation model was used whereby left lungs underwent 1 h ischemia 2 reperfusion. Treatment wild-type mice with...
Increasing prevalence of obesity and its associated risk with cardiovascular diseases demands a better understanding the contribution different cell types within this complex disease for developing new treatment options. Previous studies could prove fundamental role FTO (fat mass obesity-associated protein) obesity; however, functional is less understood.We identify endothelial as previously unknown central regulator both obesity-induced metabolic vascular alterations.We generated...
BACKGROUND: Hypertension incidence increases with age and represents one of the most prevalent risk factors for cardiovascular disease. Clonal events in hematopoietic system resulting from somatic mutations driver genes are elderly individuals who lack overt hematologic disorders. This condition is referred to as age-related clonal hematopoiesis (CH), it a newly recognized factor It not known whether CH hypertension causally related and, if so, what mechanistic features. METHODS: A murine...
Ischemic stroke is a leading cause of morbidity and mortality in the US; however, there currently exists only one effective acute pharmacological therapeutic intervention. Purinergic signaling has been shown to regulate vascular function pathological processes, including inflammation arterial myogenic reactivity, plays role ischemic outcome. requires extracellular purines; mechanism purine release from cells unclear. Pannexin1 (Panx1) channels are potentially novel expressed throughout tree...
A pathway underlying the TNFα-induced decrease in endothelial barrier function is found veins but not arteries.
Abstract Ischemic stroke is a leading cause of morbidity and mortality. We have previously shown that deletion endothelial cell (EC) Panx1 reduces ischemic infarct volume cerebral arterial myogenic reactivity, which regulates blood flow. hypothesized EC content dictates outcome thus increased expression will worsen outcomes due to exacerbated tone development impaired flow recovery. To test this, we generated the Cdh5-Cre ERT2+ ROSA26-hPanx1 Tg mouse model conditionally overexpresses human...
Arteriolar endothelial cell–expressed (EC-expressed) α-globin binds NOS (eNOS) and degrades its enzymatic product, NO, via dioxygenation, thereby lessening the vasodilatory effects of NO on nearby vascular smooth muscle. Although this reaction potentially affects physiology, mechanisms that regulate expression dioxygenase activity in ECs are unknown. Without β-globin, is unstable cytotoxic, particularly oxidized form, which generated by dioxygenation recycled endogenous reductases. We show...
Extracellular vesicles (EVs) have been described as novel biomarkers and bioactivators in vascular dysfunction hypertension. However, the mechanism(s) by which EVs affect function is unknown. To examine effects of on endothelial-dependent vasodilation (acetylcholine), we isolated circulating from platelet-poor plasma using a low centrifugation speed (17 000 g ) mesenteric resistance arteries 12-week-old normotensive WKYs (Wistar-Kyoto rats) SHRs (spontaneously hypertensive rats). Arteries...
The purpose of this study was to determine the sweat rate and electrolyte composition in female international level soccer players. Thirteen players performed two 90 min soccer-specific training sessions (T1 T2) on separate days. Hydration status determined prior each session loss, (Na+, K+, Mg++ Ca+) were from patches worn during training. mean T1 T2 0.50±0.20 0.43±0.18 L.h−1 respectively (P>0.05). was: [Na+]: 43.9±15.0 46.2±7.9 mmol.L−1; [K+]: 6.1±1.1 5.2±1.1 [Mg++]: 0.1±0.0 [Ca+]: 1.2±0.5...
Objective- Sympathetic nerve innervation of vascular smooth muscle cells (VSMCs) is a major regulator arteriolar vasoconstriction, resistance, and blood pressure. Importantly, α-adrenergic receptor stimulation, which uniquely couples with Panx1 (pannexin 1) channel-mediated ATP release in resistance arteries, also requires localization to membrane caveolae. Here, we test whether Cav1 (caveolin-1) promotes channel function (stimulus-dependent adrenergic vasoconstriction) important for...
Resistance arteries and conduit rely on different relative contributions of endothelial-derived hyperpolarization versus nitric oxide to achieve dilatory heterocellular signaling. Anatomically, resistance use myoendothelial junctions (MEJs), endothelial cell projections that make contact with smooth muscle cells. Conduit have very few no MEJs.Determine if the presence MEJs in can alter signaling.We previously demonstrated PAI-1 (plasminogen activator inhibitor-1) regulate formation MEJs....
The arterial vasculature can be divided into large conduit arteries, intermediate contractile resistance arterioles, and capillaries. Resistance arteries arterioles primarily function to control systemic blood pressure. are composed of a layer endothelial cells oriented parallel the direction flow, which separated by matrix termed internal elastic lamina from several layers smooth muscle perpendicular flow. Cells within vessel walls communicate in homocellular heterocellular fashion govern...
Coronary microvascular disease (CMD) caused by obesity and diabetes is major contributor to heart failure with preserved ejection fraction; however, the mechanisms underlying CMD are not well understood. Using cardiac magnetic resonance applied mice fed a high-fat, high-sucrose diet as model of CMD, we elucidated role inducible nitric oxide synthase (iNOS) 1400W, an iNOS antagonist, in CMD. Global deletion prevented along associated oxidative stress diastolic subclinical systolic...
Abstract Wound healing is facilitated by neoangiogenesis, a complex process that essential to tissue repair in response injury. MicroRNAs are small, noncoding RNAs can regulate the wound including stimulation of impaired angiogenesis associated with type‐2 diabetes (T2D). Expression miR‐409‐3p was significantly increased nonhealing skin wounds patients T2D compared non‐wounded normal skin, and murine model T2D. In high glucose, neutralization markedly improved EC growth migration human...
PerspectivesThe Pathophysiology of COVID-19 and SARS-CoV-2 InfectionConsideration Pannexin 1 channels in pathology treatmentLeigh Anne Swayne, Scott R. Johnstone, Chen Seng Ng, Juan C. Sanchez-Arias, Miranda E. Good, Silvia Penuela, Alexander W. Lohman, Abigail G. Wolpe, Victor Laubach, Michael Koval, Brant IsaksonLeigh SwayneDivision Medical Sciences, University Victoria, British Columbia, Canada, JohnstoneFralin Biomedical Research Institute at Virginia Tech Carilion Center for Heart...
Connexin 37 (Cx37) profoundly suppresses the proliferation of rat insulinoma (Rin) cells by unknown mechanisms. To determine whether a functional pore domain is necessary for Cx37-mediated growth suppression, we introduced mutation that converted threonine 154 into alanine (T154A). Like other connexins mutated at homologous site, Cx37-T154A localized to appositional membrane but failed form channels and exerted dominant-negative effect on coexpressed wild-type Cx37 or Cx43. Unlike protein,...
The ability of hemoglobin to scavenge the potent vasodilator nitric oxide (NO) in blood has been well established as a mechanism vascular tone homeostasis. In endothelial cells, alpha chain (hereafter, globin) and NO synthase form macromolecular complex, providing sink for directly adjacent production source. We have developed an globin mimetic peptide (named HbαX) that displaces endogenous increases bioavailable vasodilation. Here we show that, vivo, HbαX administration capillary...
Objective— In resistance arteries, endothelial cell (EC) extensions can make contact with smooth muscle cells, forming myoendothelial junction at holes in the internal elastic lamina (HIEL). At these HIEL, calcium signaling is tightly regulated. Because Calr (calreticulin) buffer ≈50% of endoplasmic reticulum and expressed throughout IEL small only place where junctions form, we investigated effect EC-specific deletion on vascular function. Approach Results— We found nearly every hole...