• Cell drinking: a closer look at how macropinocytosis drives cholesterol uptake in atherosclerotic vessels

      Lin, Huiping; Vascular Biology Center (Augusta University, 2020-05)
      Atherosclerotic vascular disease is the underlying cause of myocardial infarction, stable and unstable angina, stroke, peripheral artery disease and sudden cardiac death. Collectively, these cardiovascular diseases are responsible for the majority of deaths worldwide. Internalization of modified apolipoprotein B–containing lipoproteins by macrophages through scavenger receptor (SR)-mediated pathways is generally viewed as an essential step for the initiation and progression of atherosclerosis. Our studies were designed to investigate the contribution of receptor-independent LDL macropinocytosis to arterial lipid accumulation and atherosclerosis. We developed novel genetic and pharmacological approaches, utilized high resolution imaging techniques and employed unique in vivo lipid quantification assays to investigate the role of macrophage macropinocytosis in the pathogenesis of atherosclerosis. My results demonstrate that the macropinocytosis inhibitor EIPA and selective deletion of a key pathway regulating macropinocytosis in myeloid cells substantially decreased lesion size in both hypercholesterolemic wild type (WT) and SR knockout (CD36-/-/SR-A-/-) mice. Stimulation of macropinocytosis using genetic and physiologically relevant approaches promotes lipoprotein internalization by WT and CD36-/-/SR-A-/- macrophages, leading to foam cell formation. Serial section high-resolution imaging of murine and human atherosclerotic arteries identified for the first time subendothelial macrophages for the first time that demonstrate plasma membrane ruffling, cupping and macropinosome internalization. Immunoelectron microscopy, 3D reconstruction of macrophage foam cells and in vivo LDL tracking demonstrate macrophage internalization of LDL in human and murine atherosclerotic arteries via macropinocytosis. We next performed a large, unbiased-screen of an FDA-approved drug library to identify clinically relevant therapeutic agents that can be repurposed as pharmacological inhibitors of macropinocytosis. Our studies identified a low MW compound (imipramine) that inhibits macrophage macropinocytosis in vitro and in vivo. Imaging, toxicity and selectivity studies demonstrated that imipramine is a potent (IC50 = 130.9 nM), non-toxic (selectivity index CC50/IC50 > 300) and selective inhibitor of macropinocytosis. Repurposing of imipramine to inhibit macropinocytosis in hypercholesterolemic mice substantially decreased plaque development compared with control treatment. Taken together, our findings challenge the SR paradigm of atherosclerosis and identify inhibition of receptor-independent macrophage macropinocytosis as a new therapeutic strategy that may be beneficial in the treatment of atherosclerosis and its cardiovascular consequences.
    • Neurovascular Injury After Retinal Ischemia Reperfusion Insult: Contrasting Roles Of Arginase Enzyme Isoforms

      Shosha, Esraa; Vascular Biology Center (2016-03-08)
      Purpose: We have previously shown the involvement of arginase enzyme in retinal neurovascular injury. The present study was undertaken to determine the distinct roles of arginase 1 (A1) and arginase 2 (A2) in neurovascular damage following ischemia/reperfusion (I/R) injury. Methods: We used wild type (WT) mice, A2 knock out mice (A2-/-) and mice lacking one copy of A1 (A1+/-). Western blotting, RT-PCR, vascular digests, immunofluorescence, Propidium Iodide (PI) labeling and electroretinography (ERG) were used to evaluate retinal injury and function. Results: I/R injury caused significant increases in A2 expression along with thinning of the neural retina, decreases in NeuN+ GCL neurons and formation of acellular capillaries. Increases in PI labeling and RIP-3 expression showed that cell death occurred by necroptosis. Neurovascular injury was accompanied by microglial activation along with increased expression of GFAP and impairment of the ERG. Neuronal cell loss, capillary degeneration, necroptosis, gliosis and ERG impairment were all significantly reduced by deletion of A2. On the other hand, A1 deletion exacerbated I/R-induced neuronal and vascular injury and further increased necroptosis and gliosis as compared with WT retinas. Conclusions: This study shows for the first time the different roles of arginase isoforms after I/R insult. I/R-induced necrotic cell death and gliosis are mediated by A2, whereas upregulation of A1 may play a role in limiting the pathology.
    • Molecular Mechanisms Underlying ATP- And Adenosine Induced Microvascular Endothelial Barrier Preservation

      Batori, Robert; Vascular Biology Center (2016-03)
      Endothelial barrier integrity has critical importance in vascular homeostasis. Disruption of the endothelial cell (EC) barrier results in increased vascular permeability. Extracellular purines, ATP and adenosine (Ado) can restore the barrier function, involving the activation of myosin light chain phosphatase (MLCP). Both ATP and Ado increase protein kinase-A (PKA) activity, however a direct link between purine-induced EC barrier enhancement, MLCP and PKA was not described. Here we show that Ado and a stable analog of ATP, ATPγS, induced human lung microvascular EC (HLMVEC) barrier enhancement and PKA activation leads to decrease in MLC and MYPT1T696 phosphorylation. Surprisingly, PKA catalytic subunit (PKAc) depletion attenuates ATPγS, but not Ado-induced increase in transendothelial electrical resistance (TER), indicating that PKA activation is involved in ATP-induced EC barrier enhancement. Depletion of PKAc leads to increase in MLC and MYPTT696 phosphorylation in ATPγS challenged EC supporting the role of PKA in MLCP activation. To elucidate the role of PKA signaling in ATP-induced EC barrier enhancement we depleted several PKA-anchoring proteins (AKAPs). AKAP2 depletion attenuates ATPγS, but not Ado-induced TER increase. Furthermore, AKAP2 co-immunoprecipitates with MYPT1. This interaction was also confirmed by PLA. In conclusion ATP- and Ado-induced barrier enhancement requires different signaling with PKA promoting ATP-, but not Ado-induced EC barrier strengthening.
    • Dissecting the Roles of Reactive Oxygen Species in Cardiovascular Disease

      Wang, Yusi; Vascular Biology Center (2015-09)
      Cardiovascular disease remains the leading cause of death in the USA. While much has been learned about the root causes, the underlying mechanisms remain incompletely understood. In particular, elevated levels of reactive oxygen species (ROS) have been observed in the vasculature of blood vessels from animal models and humans with hypertension, atherosclerosis and diabetes. The importance of ROS to cardiovascular disease and the mechanisms by which it alters the function of cells of the cardiovascular system are the goals of this dissertation.
    • The role of the transcription factor, Sox18, in pulmonary endothelial barrier function

      Gross, Christine M; Vascular Biology Center (2014-12)
      Pulmonary endothelial cells form a continuous monolayer on the luminal surface of the lung vasculature. These cells provide a surface for gas exchange and importantly regulate vascular tone. Despite being constantly exposed to hemodynamic forces and/or vasoactive agents, the endothelium also maintains a selectively permeable monolayer under physiologic conditions. However, little is known about the transcriptional events in the pulmonary endothelium that regulate the paracellular barrier under normal conditions or when the cells are exposed to pathological factors such as increased shear stress from congenital heart abnormalities (shunt), lipopolysaccharide (LPS) from the outer membrane of gram negative bacteria, or increased cyclic stretch from mechanical ventilation. Shear stress has been shown to increase, while LPS and cyclic strain have been shown to decrease, alveolar-capillary barrier function. The transcription factor, Sox18, is known to play a key role in regulating vascular development. Here, in ovine pulmonary arterial endothelial cells (PAEC) subjected to physiologic levels of laminar flow (20 dyn/cm2), we identified an increase in trans-endothelial resistance (TER) that correlated with an increase in Sox18 expression. Further, we found that shear stress up-regulated the cellular tight junction protein, Claudin-5, in a Sox18 dependent manner, and Claudin-5 depletion abolished the Sox18 mediated increase in TER in response to shear stress. Utilizing peripheral lung tissue of 4 week old shunt lambs with increased pulmonary blood flow, we found that both Sox18 and Claudin-5 mRNA and protein levels were elevated. In contrast, in human lung microvascular endothelial cells (HLMVEC) exposed to LPS (1EU/ml) for 4 h, the mRNA and protein levels of Sox18 and Claudin-5 were decreased in an NF-κB (p65) and HDAC dependent manner. Sox18 over-expression prevented the LPS dependent loss of TER. Interestingly, this barrier protective effect of Sox18 was abolished by Claudin-5 silencing. In mice given an intratracheal instillation of LPS (2mg/kg, 24 h), we found that the over-expression of Sox18 in the pulmonary vasculature significantly increased Claudin-5 expression and attenuated the LPS mediated increase in lung vascular leak, inflammatory cell infiltration, and inflammatory cytokines in the bronchoalveolar lavage fluid. Sox18 gene delivery also increased oxygen saturation and improved lung function in LPS exposed mice. Similarly, in mice ventilated with high tidal volumes (HTV; 30 ml/kg, 75 bpm, 0.5 FiO2) for 8 h, Sox18 and Claudin-5 protein levels were reduced. However, Sox18 over-expression significantly increased Claudin-5 expression and improved lung function in HTV exposed mice. Together, our study demonstrates that Sox18 is an important regulator of pulmonary endothelial barrier function.
    • Insights into the Arginine Paradox and the Role of Arginase in Diabetic Retinopathy

      Elms, Shawn; Vascular Biology Center (2012-12)
      Reduced production of nitric oxide (NO) is one of the first indications of endothelial dysfunction and precedes the development of many cardiovascular diseases. Arginase has been shown to be upregulated in cardiovascular disease and has been proposed as a mechanism to account for diminished NO production. Arginases consume L-arginine, the substrate for nitric oxide synthase (NOS), and L-arginine depletion is thought to reduce NOS-derived NO. However, this simple relationship is complicated by the L-arginine paradox. The paradox addresses the phenomenon that L-arginine concentrations in endothelial cells remain sufficiently high to support NO synthesis yet increasing Larginine externally drives increased production of NO. One mechanism proposed to explain this is compartmentalization of intracellular L-arginine into distinct pools. In the current study we investigated this concept by targeting eNOS and arginase to different locations within the cell. We first showed that supplemental L-arginine and L-citrulline dose-dependently increased NO production in a manner independent of the location of eNOS within the cell. Cytosolic arginase-1 (ArgI) and mitochondrial arginase-2 (Argil) inhibited eNOS activity equally regardless of where in the cell eNOS was expressed. Similarly, targeting ArgI to different regions of the cell did not modify its ability to inhibit NO formation. These results argue against compartmentalization as the mechanism by which arginase inhibit eNOS. Further studies showed that arginasedependent inhibition of NO formation was prevented pharmacologically with arginase inhibitors. Also, arginase inhibition of NO production was absent in a catalytically inactive arginase mutant. Arginase did not co-immunoprecipitate with eNOS and the metabolic products of arginase or downstream enzymes did not contribute to reduced NO formation. Because of previous studies in animals and cell culture supporting the role of ArgI specifically in vascular dysfunction, we aimed to investigate the role of ArgI in the retinal vascular dysfunction of diabetic retinopathy (DR). Our hypothesis was that ArgI could be a mediator in the vascular dysfunction associated with DR. While using a mouse funduscope to image the retinal vasculature, we infused acetylcholine or sodium nitroprasside intravenously into diabetic or normoglycemic control mice and measured vessel relaxation. Endothelium-dependent retinal vasorelaxation was impaired in diabetic mice (40% of control). Diabetic mice hemizygous for arginase-1 (Argl+/") had improved function of the retinal vessels (71% of control). Endothelium-independent vasorelaxation was similar in diabetic and control, Argl+/' and wild type mice, indicating that the diabetes effect was specifically an endothelial issue and not one of smooth muscle dysfunction. Arginase inhibitors were shown to be effective in improving vascular function and reducing arginase activity. Further experiments were conducted in isolated central retinal arteries of diabetic and control rats, which recapitulated the results found in the mouse. We found that pharmacologic inhibition in both mice and rats or partial knock out of ArgI in mice resulted in improvement in the retinal vascular dysfunction associated with DR. We conclude that ArgI is a potential player in the retinal vascular dysfunction of DR.
    • PPAR-c Regulates Carnitine Homeostasis and Mitochondrial Function in a Lamb Model of Increased Pulmonary Blood Flow

      Sharma, Shruti; Sun, Xutong; Rafikov, Ruslan; Kumar, Sanjiv; Hou, Yali; Oishi, Peter E.; Datar, Sanjeev A.; Raff, Gary; Fineman, Jeffrey R.; Black, Stephen M.; et al. (2012-09-4)
      Objective: Carnitine homeostasis is disrupted in lambs with endothelial dysfunction secondary to increased pulmonary blood flow (Shunt). Our recent studies have also indicated that the disruption in carnitine homeostasis correlates with a decrease in PPAR-c expression in Shunt lambs. Thus, this study was carried out to determine if there is a causal link between loss of PPAR-c signaling and carnitine dysfunction, and whether the PPAR-c agonist, rosiglitazone preserves carnitine homeostasis in Shunt lambs.
    • Oxygen Glucose Deprivation in Rat Hippocampal Slice Cultures Results in Alterations in Carnitine Homeostasis and Mitochondrial Dysfunction

      Rau, Thomas F.; Lu, Qing; Sharma, Shruti; Sun, Xutong; Leary, Gregory; Beckman, Matthew L.; Hou, Yali; Wainwright, Mark S.; Kavanaugh, Michael; Poulsen, David J.; et al. (2012-09-11)
      Mitochondrial dysfunction characterized by depolarization of mitochondrial membranes and the initiation of mitochondrial-mediated apoptosis are pathological responses to hypoxia-ischemia (HI) in the neonatal brain. Carnitine metabolism directly supports mitochondrial metabolism by shuttling long chain fatty acids across the inner mitochondrial membrane for beta-oxidation. Our previous studies have shown that HI disrupts carnitine homeostasis in neonatal rats and that L-carnitine can be neuroprotective. Thus, this study was undertaken to elucidate the molecular mechanisms by which HI alters carnitine metabolism and to begin to elucidate the mechanism underlying the neuroprotective effect of L-carnitine (LCAR) supplementation. Utilizing neonatal rat hippocampal slice cultures we found that oxygen glucose deprivation (OGD) decreased the levels of free carnitines (FC) and increased the acylcarnitine (AC): FC ratio. These changes in carnitine homeostasis correlated with decreases in the protein levels of carnitine palmitoyl transferase (CPT) 1 and 2. LCAR supplementation prevented the decrease in CPT1 and CPT2, enhanced both FC and the ACâ ¶FC ratio and increased slice culture metabolic viability, the mitochondrial membrane potential prior to OGD and prevented the subsequent loss of neurons during later stages of reperfusion through a reduction in apoptotic cell death. Finally, we found that LCAR supplementation preserved the structural integrity and synaptic transmission within the hippocampus after OGD. Thus, we conclude that LCAR supplementation preserves the key enzymes responsible for maintaining carnitine homeostasis and preserves both cell viability and synaptic transmission after OGD.
    • Notch2 and Notch3 Function Together to Regulate Vascular Smooth Muscle Development

      Wang, Qingqing; Zhao, Ning; Kennard, Simone; Lilly, Brenda; Vascular Biology Center (2012-05-17)
      Notch signaling has been implicated in the regulation of smooth muscle differentiation, but the precise role of Notch receptors is ill defined. Although Notch3 receptor expression is high in smooth muscle, Notch3 mutant mice are viable and display only mild defects in vascular patterning and smooth muscle differentiation. Notch2 is also expressed in smooth muscle and Notch2 mutant mice show cardiovascular abnormalities indicative of smooth muscle defects. Together, these findings infer that Notch2 and Notch3 act together to govern vascular development and smooth muscle differentiation. To address this hypothesis, we characterized the phenotype of mice with a combined deficiency in Notch2 and Notch3. Our results show that when Notch2 and Notch3 genes are simultaneously disrupted, mice die in utero at mid-gestation due to severe vascular abnormalities. Assembly of the vascular network occurs normally as assessed by Pecam1 expression, however smooth muscle cells surrounding the vessels are grossly deficient leading to vascular collapse. In vitro analysis show that both Notch2 and Notch3 robustly activate smooth muscle differentiation genes, and Notch3, but not Notch2 is a target of Notch signaling. These data highlight the combined actions of the Notch receptors in the regulation of vascular development, and suggest that while these receptors exhibit compensatory roles in smooth muscle, their functions are not entirely overlapping.
    • Intracellular Kinases Mediate Increased Translation and Secretion of Netrin-1 from Renal Tubular Epithelial Cells

      Jayakumar, Calpurnia; Mohamed, Riyaz; Ranganathan, Punithavathi Vilapakkam; Ramesh, Ganesan; Vascular Biology Center (2011-10-26)
      Background: Netrin-1 is a laminin-related secreted protein, is highly induced after tissue injury, and may serve as a marker of injury. However, the regulation of netrin-1 production is not unknown. Current study was carried out in mouse and mouse kidney cell line (TKPTS) to determine the signaling pathways that regulate netrin-1 production in response to injury.
    • Arginase 2 Deletion Reduces Neuro-Glial Injury and Improves Retinal Function in a Model of Retinopathy of Prematurity

      Narayanan, Subhadra P.; Suwanpradid, Jutamas; Saul, Alan; Xu, Zhimin; Still, Amber; Caldwell, Robert William; Caldwell, Ruth B.; Vascular Biology Center; Department of Cellular Biology and Anatomy; Department of Ophthalmology; et al. (2011-07-21)
      Background: Retinopathy of prematurity (ROP) is a major cause of vision impairment in low birth weight infants. While previous work has focused on defining the mechanisms of vascular injury leading to retinal neovascularization, recent studies show that neurons are also affected. This study was undertaken to determine the role of the mitochondrial arginine/ornithine regulating enzyme arginase 2 (A2) in retinal neuro-glial cell injury in the mouse model of ROP.
    • Inflammation and diabetic retinal microvascular complications

      Zhang, Wenbo; Liu, Hua; Al-Shabrawey, Mohamed; Caldwell, Robert William; Caldwell, Ruth B.; Vascular Biology Center; Vision Discovery Institute; Department of Pharmacology and Toxicology; Department of Oral Biology; Department of Cellular Biology and Anatomy; et al. (2011-04)
      Diabetic retinopathy (DR) is one of the most common complications of diabetes and is a leading cause of blindness in people of the working age in Western countries. A major pathology of DR is microvascular complications such as non-perfused vessels, microaneurysms, dot/blot hemorrhages, cotton-wool spots, venous beading, vascular loops, vascular leakage and neovascularization. Multiple mechanisms are involved in these alternations. This review will focus on the role of inflammation in diabetic retinal microvascular complications and discuss the potential therapies by targeting inflammation.
    • CXCL9 induces chemotaxis, chemorepulsion and endothelial barrier disruption through CXCR3-mediated activation of melanoma cells

      Amatschek, S; Lucas, Rudolf; Eger, Andreas; Pflueger, M; Hundsberger, Harald; Knoll, C; Grosse-Kracht, S; Schuett, W; Koszik, F; Maurer, D; et al. (2011-02-01)
      Background
    • P2Y receptors as regulators of lung endothelial barrier integrity

      Zemskov, Evgeny A.; Lucas, Rudolf; Verin, Alexander D.; Umapathy, Nagavedi S.; Vascular Biology Center; Department of Pulmonary and Critical Care (2011-01)
      Endothelial cells (ECs), forming a semi-permeable barrier between the interior space of blood vessels and underlying tissues, control such diverse processes as vascular tone, homeostasis, adhesion of platelets, and leukocytes to the vascular wall and permeability of vascular wall for cells and fluids. Mechanisms which govern the highly clinically relevant process of increased EC permeability are under intense investigation. It is well known that loss of this barrier (permeability increase) results in tissue inflammation, the hall mark of inflammatory diseases such as acute lung injury and its severe form, acute respiratory distress syndrome. Little is known about processes which determine the endothelial barrier enhancement or protection against permeability increase. It is now well accepted that extracellular purines and pyrimidines are promising and physiologically relevant barrier-protective agents and their effects are mediated by interaction with cell surface P2Y receptors which belong to the superfamily of G-protein-coupled receptors. The therapeutic potential of P2Y receptors is rapidly expanding field in pharmacology and some selective agonists became recently available. Here, we present an overview of recently identified P2Y receptor agonists that enhance the pulmonary endothelial barrier and inhibit and/or reverse endothelial barrier disruption.
    • Allele Polymorphism and Haplotype Diversity of HLA-A, -B and -DRB1 Loci in Sequence-Based Typing for Chinese Uyghur Ethnic Group

      Deng, Ya-jun; Ye, Shi-hui; Yan, Jiang-wei; Yang, Guang; Wang, Hong-dan; Qin, Hai-xia; Huang, Qi-zhao; Zhang, Jing-Jing; Shen, Chun-mei; Zhu, Bo-feng; et al. (2010-11-04)
      Background: Previous studies indicate that the frequency distributions of HLA alleles and haplotypes vary from one ethnic group to another or between the members of the same ethnic group living in different geographic areas. It is necessary and meaningful to study the high-resolution allelic and haplotypic distributions of HLA loci in different groups.
    • Notch3 Signaling Mediates Heterotypic Cell Interactions During Blood Vessel Formation

      Liu, Hua; Vascular Biology Center (2010-11)
      Blood vessel formation is essential for embryogenesis, wound healing, menstruation, and pregnancy [1, 2]. While much emphasis has been placed on understanding the initial event of endothelial-tube formation, relatively little attention has been paid to the interactions of endothelial cells and the surrounding mural cells (pericytes, smooth muscle cells and fibroblasts). Increasing evidence suggests that the communication of endothelial cells and mural cells is crucial for the assembly, subsequent maturation, and stabilization of blood vessels [3-5]. Abnormal interactions between these two cell types have been implicated in many pathological conditions, including tumor angiogenesis, diabetic microangiopathy, tissue calcification and stroke. However, the molecules mediating the heterotypic interaction are still largely unknown. Our previous studies have shown that in a three-dimensional (3-D) angiogenesis assay, mural cells enhance blood vessel formation and directly interact with endothelial cells [6]. During this process, Notch3 is one gene that is strongly induced in mural cells upon coculture with endothelial cells [6]. Notch3, the causative gene of the neurovascular disorder CADASIL [7], belongs to an evolutionarily conserved family of transmembrane receptors that are known to govern cell fate determination in diverse cell types [8]. Given that Notch receptors and ligands are expressed on both endothelial and mural cells and - 2 - Notch3 is upregulated in mural cells by coculturing with endothelial cells, it is reasonable to assume that the Notch3 receptor might regulate the association of endothelial and mural cells through receptor-ligand interaction during blood vessel formation. The goal of my thesis is to investigate how Notch3 gene expression is regulated in mural cells by endothelial cells and whether the Notch3 receptor is involved in the communication between endothelial and mural cells during blood vessel formation. To achieve these goals, three aims were proposed: Specific Aim 1: To define how Notch3 expression in mural cells is upregulated by endothelial cells. Specific Aim 2: To determine if endothelial cell-induced Notch3 expression is critical for mural cell differentiation. Specific Aim 3: To determine whether Notch3 expression in mural cells modulates blood vessel formation under both physiological and pathological conditions.
    • Microtubules growth rate alteration in human endothelial cells.

      Alieva, Irina B; Zemskov, Evgeny A.; Kireev, Igor I; Gorshkov, Boris A; Wiseman, Dean A; Black, Stephen M.; Verin, Alexander D.; Vascular Biology Center (2010-05-06)
      To understand how microtubules contribute to the dynamic reorganization of the endothelial cell (EC) cytoskeleton, we established an EC model expressing EB3-GFP, a protein that marks microtubule plus-ends. Using this model, we were able to measure microtubule growth rate at the centrosome region and near the cell periphery of a single human EC and in the EC monolayer. We demonstrate that the majority of microtubules in EC are dynamic, the growth rate of their plus-ends is highest in the internal cytoplasm, in the region of the centrosome. Growth rate of microtubule plus-ends decreases from the cell center toward the periphery. Our data suggest the existing mechanism(s) of local regulation of microtubule plus-ends growth in EC. Microtubule growth rate in the internal cytoplasm of EC in the monolayer is lower than that of single EC suggesting the regulatory effect of cell-cell contacts. Centrosomal microtubule growth rate distribution in single EC indicated the presence of two subpopulations of microtubules with "normal" (similar to those in monolayer EC) and "fast" (three times as much) growth rates. Our results indicate functional interactions between cell-cell contacts and microtubules.
    • Novel mechanisms of endothelial dysfunction in diabetes

      Yang, Guang; Lucas, Rudolf; Caldwell, Ruth B.; Yao, Lin; Romero, Maritza J.; Caldwell, Robert William; Vascular Biology Center; Department of Pharmacology and Toxicology (2010-04)
      Diabetes mellitus is a major risk factor for cardiovascular morbidity and mortality. This condition increases the risk of developing coronary, cerebrovascular, and peripheral arterial disease fourfold. Endothelial dysfunction is a major contributor to the pathogenesis of vascular disease in diabetes mellitus patients and has recently received increased attention. In this review article, some recent developments that could improve the knowledge of diabetes-induced endothelial dysfunction are discussed.
    • Regulation of soluble guanylyl cyclase by phosphorylation

      Zhou, Zongmin; Sayed, Nazish; Pyriochou, Anastasia; Fulton, David; Beuve, Annie; Papapetropoulos, Andreas; Vascular Biology Center (2009-08-11)
    • Regulation of soluble guanylyl cyclase by phosphorylation

      Zhou, Zongmin; Sayed, Nazish; Pyriochou, Anastasia; Fulton, David; Beuve, Annie; Papapetropoulos, Andreas; Vascular Biology Center (2009-08-11)