A5060290731- Nitric Oxide and Endothelin Effects
- Protein Kinase Regulation and GTPase Signaling
- Adenosine and Purinergic Signaling
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Cell Adhesion Molecules Research
- Protease and Inhibitor Mechanisms
- S100 Proteins and Annexins
- Pulmonary Hypertension Research and Treatments
- Angiogenesis and VEGF in Cancer
- Cellular Mechanics and Interactions
- Blood Coagulation and Thrombosis Mechanisms
- Neonatal Respiratory Health Research
- Eicosanoids and Hypertension Pharmacology
- Ion Transport and Channel Regulation
- Caveolin-1 and cellular processes
- Signaling Pathways in Disease
- Ion channel regulation and function
- Histone Deacetylase Inhibitors Research
- Mitochondrial Function and Pathology
- Immune Response and Inflammation
- Microtubule and mitosis dynamics
- Respiratory Support and Mechanisms
- Cancer, Hypoxia, and Metabolism
- Barrier Structure and Function Studies
- ATP Synthase and ATPases Research
Augusta University
2016-2025
Center for Vascular Biology Research
2009-2025
Augusta University Health
2013-2024
Georgia Regents Medical Center
2013-2016
Pulmonary Associates
2008-2014
Pulmonary and Critical Care Associates
2013-2014
Walker (United States)
2007-2013
University of Chicago
2005-2007
Johns Hopkins University
1999-2006
Johns Hopkins Medicine
1999-2006
Substances released by platelets during blood clotting are essential participants in events that link hemostasis and angiogenesis ensure adequate wound healing tissue injury repair. We assessed the participation of sphingosine 1-phosphate (Sph-1-P), a biologically active phosphorylated lipid growth factor from activated platelets, regulation endothelial monolayer barrier integrity, which is key to both vascular homeostasis. Sph-1-P produced rapid, sustained, dose-dependent increases...
Tumor necrosis factor (TNF)-alpha, a major proinflammatory cytokine, triggers endothelial cell activation and barrier dysfunction which are implicated in the pathogenesis of pulmonary edema associated with acute lung injury syndromes. The mechanisms TNF-alpha-induced vascular permeability not completely understood. Our initial experiments demonstrated that decreases transendothelial electrical resistance across human artery cells independent myosin light chain phosphorylation catalyzed by...
Ventilator-induced lung injury syndromes are characterized by profound increases in vascular leakiness and activation of inflammatory processes. To explore whether excessive cyclic stretch (CS) directly causes barrier disruption or enhances endothelial cell sensitivity to edemagenic agents, human pulmonary artery cells (HPAEC) were exposed physiologically (5% elongation) pathologically (18% relevant levels strain. CS produced rapid (10 min) myosin light chain (MLC) phosphorylation, p38...
Tumor necrosis factor (TNF)-α is released in acute inflammatory lung syndromes linked to the extensive vascular dysfunction associated with increased permeability and endothelial cell apoptosis. TNF-α induced significant decreases transcellular electrical resistance across pulmonary monolayers, reflecting barrier (beginning at 4 h persisting for 48 h). also triggered apoptosis beginning h, which was attenuated by caspase inhibitor Z-Val-Ala-Asp-fluoromethylketone. Exploring involvement of...
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The phosphorylation of myosin light chains by chain kinase (MLCK) is a key event in agonist-mediated endothelial cell gap formation and vascular permeability. We now report the cloning expression nonmuscle MLCK isoform cultured endothelium. Screening human cDNA library identified 7.7 kb with substantial (> 95%) homology to coding region rabbit bovine smooth muscle (SM) (amino acid #923-1913) as well reported avian (65-70% homology). Sequence analysis also identified, however, 5' stretch...
Disturbances in endothelial cell (EC) barrier regulation are critically dependent upon rearrangements of EC actin cytoskeleton. However, the role microtubule (MT) network permeability is not well understood. We examined involvement MT remodeling thrombin-induced and explored by heterotrimeric G12/13 proteins small GTPase Rho. Thrombin induced phosphorylation regulatory protein tau at Ser409 Ser262 peripheral disassembly, which was linked to increased permeability. stabilization taxol...
Abstract Barrier dysfunction of pulmonary endothelial monolayer is associated with dramatic cytoskeletal reorganization, activation actomyosin contractility, and gap formation. The linkage between the microtubule (MT) network contractile cytoskeleton has not been fully explored, however, clinical observations suggest that intravenous administration anti‐cancer drugs MT inhibitors (such as vinca alkaloids) can lead to sudden development edema in breast cancer patients. In this study, we...
Enhanced vascular arginase activity impairs endothelium-dependent vasorelaxation by decreasing l-arginine availability to endothelial nitric oxide (NO) synthase, thereby reducing NO production. Elevated angiotensin II (ANG II) is a key component of dysfunction in many cardiovascular diseases and has been linked elevated activity. We determined signaling mechanisms which ANG increases function. Results show that (0.1 μM, 24 h) elevates I expression bovine aortic cells (BAECs) decreases These...
Rationale: Glycolytic shift is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). It remains unknown how glycolysis increased and contributes to vascular remodeling PAH.Objectives: To determine whether caused by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) PFKFB3-driven induces PAH.Methods: PFKFB3 levels were measured arteries patients animals with PAH. Lactate assessed lungs PAH artery smooth muscle cells (PASMCs). Genetic pharmacologic approaches...
Endothelial cells (EC) form a semi-permeable barrier between the interior space of blood vessels and underlying tissues. In acute lung injury (ALI) EC is weakened leading to increased vascular permeability. It widely accepted that integrity critically dependent upon intact cytoskeletal structure cell junctions. Edemagenic agonists, like thrombin or endotoxin lipopolysaccharide (LPS), induced rearrangement, contractile responses disruption intercellular contacts permeability increase. The...
Endothelial cells (ECs) form a semi-permeable barrier between the interior space of blood vessels and underlying tissues. Pulmonary endothelial integrity is maintained through coordinated cellular processes involving receptors, signaling molecules, junctional complexes, protein-regulated cytoskeletal reorganization. In acute lung injury (ALI) or its more severe respiratory distress syndrome (ARDS), loss secondary to dysfunction caused by pulmonary inflammation and/or infection leads edema...
Endothelial cell (EC) barrier regulation is critically dependent on cytoskeletal components (microfilaments and microtubules). Because several edemagenic agents induce actomyosin-driven EC contraction tightly linked to myosin light chain (MLC) phosphorylation microfilament reorganization, we examined the role of microtubule in bovine regulation. Nocodazole or vinblastine, inhibitors polymerization, significantly decreased transendothelial electrical resistance a dose-dependent manner,...
Endothelial cell (EC) permeability is precisely controlled by cytoskeletal elements [actin filaments, microtubules (MT), intermediate filaments] and contact protein complexes (focal adhesions, adherens junctions, tight junctions). We have recently shown that the edemagenic agonist thrombin caused partial MT disassembly, which was linked to activation of small GTPase Rho, Rho-mediated actin remodeling, contraction, dysfunction lung EC barrier. GEF-H1 an MT-associated Rho-specific guanosine...
The stabilization of endothelial cell (EC) barrier function within newly formed capillaries is a critical feature angiogenesis. We examined human lung EC regulation elicited by hepatocyte growth factor (HGF), recognized angiogenic and chemoattractant. HGF rapidly dose-dependently elevated transendothelial electrical resistance (TER) monolayers (>50% increase at 100 ng/ml), with immunofluorescence microscopic evidence both cytoplasmic actin stress fiber dissolution strong augmentation the...
After an acute phase of inflammation or injury, restoration the endothelial barrier is important to regain vascular integrity and prevent edema formation. However, little known about mediators that control function. We show here oxidized phospholipids accumulate at sites tissue damage are potent regulators Oxygenated epoxyisoprostane-containing phospholipids, but not fragmented exhibited barrier-protective effects mediated by small GTPases Cdc42 Rac their cytoskeletal, focal adhesion,...
Inflammatory diseases of the lung are characterized by increases in vascular permeability and enhanced leukocyte infiltration, reflecting compromise endothelial cell (EC) barrier. We examined potential molecular mechanisms that underlie these alterations assessed effects diperoxovanadate (DPV), a potent tyrosine kinase activator phosphatase inhibitor, on EC contractile events. Confocal immunofluorescent microscopy confirmed dramatic stress-fiber formation colocalization myosin light chain...
The Ca2+/calmodulin-dependent endothelial cell myosin light chain kinase (MLCK) triggers actomyosin contraction essential for vascular barrier regulation and leukocyte diapedesis. Two high molecular weight MLCK splice variants, EC MLCK-1 MLCK-2 (210–214 kDa), in human endothelium are identical except a deleted single exon encoding 69-amino acid stretch (amino acids 436–505) that contains potentially important consensus sites phosphorylation by p60Src (Lazar, V., Garcia, J. G. (1999) Genomics...
We compared stimulus-coupling pathways involved in bovine pulmonary artery (PA) and lung microvascular endothelial cell migration evoked by sphingosine-1-phosphate (S1P), a potent bioactive lipid released from activated platelets, vascular growth factor (VEGF), well-recognized angiogenic factor. S1P-induced was maximum at 1 microM (approximately 8-fold increase with PA endothelium) surpassed the maximal response either VEGF (10 ng/ml) 2.5-fold increase) or hepatocyte (HGF) increase)....