A5030575700- Pulmonary Hypertension Research and Treatments
- Ion channel regulation and function
- Cardiac electrophysiology and arrhythmias
- Nitric Oxide and Endothelin Effects
- Ion Channels and Receptors
- Cancer, Hypoxia, and Metabolism
- Ion Transport and Channel Regulation
- Cardiovascular Function and Risk Factors
- Renin-Angiotensin System Studies
- Diabetes Treatment and Management
- Protein Kinase Regulation and GTPase Signaling
- MicroRNA in disease regulation
- RNA modifications and cancer
- Eicosanoids and Hypertension Pharmacology
- Cardiovascular, Neuropeptides, and Oxidative Stress Research
- Erythrocyte Function and Pathophysiology
- Electrochemical Analysis and Applications
- Neurobiology and Insect Physiology Research
- Hormonal Regulation and Hypertension
- Nicotinic Acetylcholine Receptors Study
- Respiratory and Cough-Related Research
- Receptor Mechanisms and Signaling
- Cardiomyopathy and Myosin Studies
- ATP Synthase and ATPases Research
- Angiogenesis and VEGF in Cancer
University of Virginia
2020-2024
University of Nevada, Reno
2007-2023
Charlottesville Medical Research
2022
University of Arizona
2014-2021
Regenerative Medicine Institute
2016
University of Illinois Chicago
2013-2015
Renown Regional Medical Center
2009
Significance Lung endothelial cells express high levels of glucose metabolic enzymes, such as PFKFB3, and consequently produce large amounts metabolites. These metabolites are able to stabilize the cell signaling molecule HIF2A, similar that which occurs under hypoxic conditions. This stabilization HIF2A by in lung stimulates production growth inflammatory factors, thereby enhancing proliferation inflammation pulmonary vessels exacerbating hypertension (PH). In this study, blockade PFKFB3...
Pulmonary vascular remodeling characterized by concentric wall thickening and intraluminal obliteration is a major contributor to the elevated pulmonary resistance in patients with idiopathic arterial hypertension (IPAH).Here we report that increased hypoxia-inducible factor 2␣ (HIF-2␣) lung endothelial cells (LVECs) under normoxic conditions involved development of (PH) inducing endothelial-to-mesenchymal transition (EndMT), which subsequently results occlusive lesions.We observed...
Endothelial dysfunction is a major player in the development and progression of vascular pathology pulmonary arterial hypertension (PAH), disease associated with small vessel loss obstructive vasculopathy that leads to increased resistance, subsequent right heart failure, premature death. Over past ten years, there has been tremendous progress our understanding endothelial biology as it pertains genetic molecular mechanisms orchestrate response direct or indirect injury, how their...
Pulmonary artery smooth muscle cells (PASMCs) are more depolarized and display higher Ca(2+) levels in pulmonary hypertension (PH). Whether the functional properties expression of Ca(2+)-activated Cl- channels (Cl(Ca)), an important excitatory mechanism PASMCs, altered PH is unknown. The potential role Cl(Ca) was investigated using monocrotaline (MCT)-induced model rat. Three weeks postinjection with a single dose MCT (50 mg/kg ip), animals developed right ventricular hypertrophy (heart...
Piezo is a mechanosensitive cation channel responsible for stretch-mediated Ca 2+ and Na + influx in multiple types of cells. Little known about the functional role Piezo1 lung vasculature its potential pathogenic pulmonary arterial hypertension (PAH). Pulmonary endothelial cells (PAECs) are constantly under mechanic stretch shear stress that sufficient to activate channels. Here, we report significantly upregulated PAECs from patients with idiopathic PAH animals experimental (PH) compared...
Inhibitors of sodium-glucose cotransporter (SGLT)2 are a new class oral drugs for type 2 diabetic patients that reduce plasma glucose levels by inhibiting renal reabsorption. There is increasing evidence showing the beneficial effect SGLT2 inhibitors on control; however, less information available regarding impact cardiovascular outcomes. The present study was designed to determine whether SGLT regulate vascular relaxation in mouse pulmonary and coronary arteries. Phlorizin (a nonspecific...
Hypoxia-induced pulmonary hypertension (HPH) is characterized by sustained vasoconstriction and vascular remodeling, both of which are mediated artery smooth muscle cell (PASMC) contraction proliferation, respectively. An increase in cytosolic Ca²⁺ concentration ([Ca²⁺]cyt) a major trigger for an important stimulus proliferation PASMCs. influx through voltage-dependent channels (VDCC) pathway the regulation [Ca²⁺]cyt. The potential role L- T-type VDCC development HPH still unclear. Using...
An increase in cytosolic free Ca(2+) concentration ([Ca(2+)]cyt) pulmonary arterial smooth muscle cells (PASMC) is a major trigger for vasoconstriction and critical stimulation PASMC proliferation migration. Previously, we demonstrated that expression function of calcium sensing receptors (CaSR) from patients with idiopathic hypertension (IPAH) animals experimental (PH) were greater than normal subjects control animals. However, the mechanisms by which CaSR triggers influx implication...
An increase in cytosolic Ca 2+ concentration ([Ca ] cyt ) pulmonary arterial smooth muscle cells (PASMC) is a major trigger for vasoconstriction and an important stimulus medial hypertrophy patients with idiopathic hypertension (IPAH). Vascular (SMC) sense the blood flow shear stress through interstitial fluid driven by pressure or direct exposure to case of endothelial injury. Mechanical can [Ca . Here we report that raised PASMC, while stress-mediated rise protein expression level TRPM7...
Concentric lung vascular wall thickening due to enhanced proliferation of pulmonary arterial smooth muscle cells is an important pathological cause for the elevated resistance reported in patients with hypertension. We identified a differential role mammalian target rapamycin (mTOR) complex 1 and 2, two functionally distinct mTOR complexes, development hypertension (PH). Inhibition attenuated PH; however, inhibition 2 caused spontaneous PH, potentially up-regulation platelet-derived growth...
The tumor-suppressive role of p53, a transcription factor that regulates the expression many genes, has been linked to cell cycle arrest, apoptosis, and senescence. noncanonical function or pathogenic p53 more recently implicated in pulmonary vascular disease. We previously reported rapid nuclear accumulation hypoxia-inducible (HIF)-1α arterial smooth muscle cells (PASMCs) upregulates transient receptor potential channels enhances Ca2+ entry increase cytosolic concentration ([Ca2+]cyt)....
An increase in cytosolic free Ca2+ concentration ([Ca2+]cyt) pulmonary artery smooth muscle cells (PASMCs) triggers vasoconstriction and stimulates PASMC proliferation leading to vascular wall thickening. Here, we report that STIM2 (stromal interaction molecule 2), a sensor the sarcoplasmic reticulum membrane, is required for raising resting [Ca2+]cyt PASMCs from patients with arterial hypertension (PAH) activating signaling cascades stimulate inhibit apoptosis. Downregulation of PAH-PASMCs...
Background and Purpose Sustained pulmonary vasoconstriction excessive vascular remodelling are two major causes of elevated resistance in patients with arterial hypertension. The purpose this study was to investigate whether chloroquine induced relaxation the artery (PA) attenuates hypoxia‐induced hypertension (HPH). Experimental Approach Isometric tension measured rat PA rings pre‐constricted phenylephrine or high K + solution. pressure mouse isolated, perfused ventilated lungs. Fura‐2...
Capsaicin is an active component of chili pepper and a pain relief drug. can activate transient receptor potential vanilloid 1 (TRPV1) channels to increase cytosolic Ca 2+ concentration ([Ca ] cyt ). A rise in [Ca pulmonary artery smooth muscle cells (PASMCs) important stimulus for vasoconstriction vascular remodeling. In this study, we observed that capsaicin-induced was significantly enhanced PASMCs from patients with idiopathic arterial hypertension (IPAH) compared normal healthy donors....
Ca 2+ signaling, particularly the mechanism via store-operated entry (SOCE) and receptor-operated (ROCE), plays a critical role in development of acute hypoxia-induced pulmonary vasoconstriction chronic hypertension. This study aimed to test hypothesis that hypoxia differentially regulates expression proteins mediate SOCE ROCE [stromal interacting molecule (STIM), Orai, canonical transient receptor potential channel TRPC6] (PASMC) coronary (CASMC) artery smooth muscle cells. The resting...
Downregulated expression of K + channels and decreased currents in pulmonary artery smooth muscle cells (PASMC) have been implicated the development sustained vasoconstriction vascular remodeling patients with idiopathic arterial hypertension (IPAH). However, it is unclear exactly how are downregulated IPAH-PASMC. MicroRNAs (miRNAs) small non-coding RNAs that capable posttranscriptionally regulating gene by binding to 3′-untranslated regions their targeted mRNAs. Here, we report specific...
Hypertension prevalence increases with age, reaching over 70% of people age 65. The underlying mechanisms are poorly understood. This study interrogates a new signaling pathway in vascular smooth muscle aged mice driven by p90 ribosomal S6 kinase, RSK2, and its role increasing peripheral resistance blood pressure (BP). Basal BP measurements were taken at 26-29 month (812-892 day) old global deletion RSK2 ( Rsk2 -/- ) prior to following treatment L-NAME. Cardiac function, vessel stiffness,...
The increase in cytosolic Ca2+ concentration ([Ca2+]cyt) and upregulation of calcium-sensing receptor (CaSR) stromal interaction molecule 2 (STIM2) along with inhibition voltage-gated K+ (KV) channels pulmonary arterial smooth muscle cells (PASMC) have been implicated the development hypertension; however, precise upstream mechanisms remain elusive. Activation CaSR, a G protein-coupled (GPCR), results release from endoplasmic/sarcoplasmic reticulum (ER/SR) influx through receptor-operated...
This study explored the mechanism by which Ca2+-activated Cl- channels (CaCCs) encoded Tmem16a gene are regulated calmodulin-dependent protein kinase II (CaMKII) and phosphatases 1 (PP1) 2A (PP2A). currents (IClCa) were recorded from HEK-293 cells expressing mouse TMEM16A. IClCa evoked using a pipette solution in free Ca2+ concentration was clamped to 500 nM, presence (5 mM) or absence of ATP. With 5 mM ATP, decayed <50% initial current magnitude within 10 min after seal rupture. rundown...
Using RNAseq, we identified a 61 gene‐based circulating transcriptomic profile most correlated with four indices of pulmonary arterial hypertension severity. In an independent dataset, 13/61 (21%) genes were differentially expressed in lung tissues cases versus controls, highlighting potentially novel candidate involved development.
Background and purpose: Ca 2+ ‐activated Cl ‐ currents (I Cl(Ca) ) in arterial smooth muscle cells are inhibited by phosphorylation. The channel (Cl blocker niflumic acid (NFA) produces a paradoxical dual effect on I , causing stimulation or inhibition at potentials below above 0 mV respectively. We tested whether the effects of NFA were modulated Experimental approach: was elicited with 500 nM free internal rabbit pulmonary artery myocytes. state global phosphorylation altered cell dialysis...
Platelet‐derived growth factor is one of the major factors found in human and mammalian serum tissues. Abnormal activation platelet‐derived signaling pathway through receptors may contribute to development progression pulmonary vascular remodeling obliterative lesions patients with arterial hypertension. In this study, we examined expression receptor isoforms smooth muscle endothelial cells investigated whether secreted from cell or promotes proliferation. Our results showed that protein α β...
Electromechanical coupling via membrane depolarization-mediated activation of voltage-dependent Ca 2+ channels (VDCC) is an important mechanism in regulating pulmonary vascular tone, while mouse animal model often used to study pathogenic mechanisms disease. The function VDCC artery (PA) smooth muscle cells (PASMC), however, has not been characterized, and their functional role reactive oxygen species (ROS)-mediated regulation remains unclear. In this study, we characterized the...