Posts in Category: Angiogenesis

Extracellular Ribonucleic Acids (RNA) Enter the Stage in Cardiovascular Disease

Extracellular Ribonucleic Acids (RNA) Enter the Stage in Cardiovascular Disease

Alma Zernecke, Klaus T. Preissner

Contribution of extracellular RNAs (eRNAs) to vascular homeostasis and cardiovascular pathologies. After cell stress (such as hypoxia, injury, and pathogen exposure), eRNA is found to be expressed at various extracellular sites, both intravascularly and extravascularly. In addition, eRNA may be derived from damaged or apoptotic cells or becomes released on inflammatory cell activation and accumulates within atherosclerotic plaques in the course of disease development. The following functional activities of eRNA are promoted by direct interactions with specific extracellular proteins: (1) promotion of vascular hyperpermeability by eRNA as coreceptor/cofactor of vascular endothelial growth factor (VEGF) and by induction of vasculogenesis/angiogenesis. (2) Initiation of intrinsic blood coagulation (via the contact phase proteins) and thrombus formation. (3) Induction of recruitment of leukocytes to the inflamed vessel wall by eRNA-mediated elevation of expression of intercellular adhesion molecule-1 in endothelial cells or vascular cell adhesion molecule-1 and P-selectin in vascular smooth muscle cells. (4) Skewing of monocytes/macrophages toward the M1 proinflammatory phenotype, accompanied by an upregulated expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-12, inducible nitric oxide synthase (iNOS), and response factors, such as chemokines. Here, eRNA triggers TNF-α–converting enzyme (TACE) to liberate the functionally active TNF-α. (5) Promotion of cardiomyocyte death by inducing a hyperinflammatory cascade involving TNF-α in the context of ischemia–reperfusion injury. [Powerpoint File]

Emerging Concepts in Paracrine Mechanisms in Regenerative Cardiovascular Medicine and Biology

Emerging Concepts in Paracrine Mechanisms in Regenerative Cardiovascular Medicine and Biology

Conrad P. Hodgkinson, Akshay Bareja, José A. Gomez, Victor J. Dzau

Paracrine factors affect different temporal events after myocardial injury influencing different stages of the reparative and regenerative processes. [Powerpoint File]

Emerging Concepts in Paracrine Mechanisms in Regenerative Cardiovascular Medicine and Biology

Emerging Concepts in Paracrine Mechanisms in Regenerative Cardiovascular Medicine and Biology

Conrad P. Hodgkinson, Akshay Bareja, José A. Gomez, Victor J. Dzau

Paracrine factors affect different cell types and create a microenvironment that is influenced by concentration gradients, with temporal and spatial summation of cellular responses. Reprinted from Hodgkinson et al149 with permission of the publisher. Copyright ©2015, Elsevier. [Powerpoint File]

Emerging Concepts in Paracrine Mechanisms in Regenerative Cardiovascular Medicine and Biology

Emerging Concepts in Paracrine Mechanisms in Regenerative Cardiovascular Medicine and Biology

Conrad P. Hodgkinson, Akshay Bareja, José A. Gomez, Victor J. Dzau

Paracrine factors are pleiotropic. For illustration, we show the cellular effects of 2 selective paracrine factors on the cardiomyocyte. Left, Hypoxic-induced Akt regulated stem cell factor (HASF) and secreted frizzled related protein 2 (Sfrp2) inhibit cardiomyocyte apoptosis through divergent pathways. HASF, after binding to a growth factor receptor, inhibits cytochrome release from mitochondria via protein kinase C-ε (PKCε). In contrast, Sfrp2 inhibits Wnt activation of frizzled receptors. This induces β-catenin degradation via the anaphase promoting complex (APC) complex. Right, Abi3bp and Sfrp2 promote cardiac progenitor cell differentiation and inhibiting proliferation. Abi3bp activates integrin-β1. Src and extracellular signal regulated kinase (ERK) activation work together to inhibit proliferation. PKCζ and Akt activation switch on cardiac genes. Sfrp2 sequesters Wnt, preventing the activation of frizzled receptors. This promotes c-Jun N-terminal kinase (JNK) activation and cardiac gene expression. Inhibition of β-catenin blocks the proliferation pathway in these cells. ECM indicates extracellular matrix; FRZ, frizzled; and TF, transcription factor. [Powerpoint File]

Cardiac Nonmyocytes in the Hub of Cardiac Hypertrophy

Cardiac Nonmyocytes in the Hub of Cardiac Hypertrophy

Takehiro Kamo, Hiroshi Akazawa, Issei Komuro

Intercellular communications between cardiomyocytes and nonmyocytes in the development of cardiac hypertrophy. Myocardial cell responses are regulated by intercellular communications between cardiomyocytes and nonmyocytes, such as fibroblasts, endothelial cells, and inflammatory cells. Cardiomyocytes secrete angiogenic factors to induce angiogenesis. An increase in capillary mass leads to increase in supply of nutrients and O2 necessary for hypertrophic growth. In addition, endothelial cells produce a variety of paracrine factors that exert prohypertrophic and antihypertrophic responses. During the development of cardiac hypertrophy, localized proliferation of both epicardium-derived and endocardium-derived fibroblast lineages contributes to extracellular matrix protein deposition and cardiac fibrosis. A wide variety of paracrine and autocrine factors mediate the intercellular communications between cardiac fibroblasts and cardiomyocytes in cardiac hypertrophy. During the development of cardiac hypertrophy, macrophages accumulate in ventricle both through localized proliferation and recruitment of circulating monocytes. Cardiac macrophages and mast cells are involved in induction of cardiac hypertrophy, although mechanistic link between T cells and the development of cardiac hypertrophy remains unclear. [Powerpoint File]

Molecular Controls of Arterial Morphogenesis

Molecular Controls of Arterial Morphogenesis

Michael Simons, Anne Eichmann

Inhibition-dependent regulation of vascular endothelial growth factor receptor 2 (VEGFR2)–driven extracellular receptor kinase (ERK) activation. A, A schematic of rapidly accelerating fibrosarcoma (Raf1) phosphorylation control. Dephosphorylation of Ser259 allows phosphorylation of Ser338 and activation of Raf1 kinase activity. B, Raf1 regulation of ERK, AKT, and MST2 pathways cross-talk. VEGFR2–induced activation of Akt leads to MST2 phosphorylation and promotes formation of Raf1–MST2 complex that maintains Raf1 in an inactive (Ser259-phosphorylated) state. Dephosphorylation of Raf1S259 site shifts MST2 to the RASSF1A (Ras association [RalGDS/AF-6] domain family member 1) complex thereby activating large tumor suppressor kinase 1 (LATS1) that subsequently acts on YAP (Yes-associated protein 1). At the same time this allows phosphorylation of Raf1Ser338 thereby activating mitogen extracellular kinase (MEK)/extracellular receptor kinase (ERK) signaling. C, Increase dorsal aorta (DA) diameter in Raf1S29A (bottom) compared with wild type (WT; top) mice. D, Extraembryonic vasculature in control (WT) and Raf1SA259 mouse embryos. Note a marked increase in arterial size. For panel B, data derived from Romano et al.104 Panels C and D adapted from Deng et al78 with permission of the publisher (American Society of Hematology, 2013). Cx40 indicates Connexin-40. [Powerpoint File]

Molecular Controls of Arterial Morphogenesis

Molecular Controls of Arterial Morphogenesis

Michael Simons, Anne Eichmann

Arteriogenic defects associated with delayed intracellular vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) trafficking. A, Micro-computed tomographic (CT) images of mouse coronary arteries from wild-type (WT; top) and Synectin null (bottom) mice. B, Micro-CT of mouse renal arterial circulation from WT (top) and myosin-VI null (bottom) mice. C, Micro-CT images of mouse heart (top), hindlimb (middle), and renal (bottom) arterial circulations from mice carrying a deletion of the neuropilin-1 (Nrp1) cytoplasmic domain. Adapted from Lanahan et al67,68 with permission of Cell Press (2013 and 2010). [Powerpoint File]

Modulating the Vascular Response to Limb Ischemia: Angiogenic and Cell Therapies

Modulating the Vascular Response to Limb Ischemia: Angiogenic and Cell Therapies

John P. Cooke, Douglas W. Losordo

Angiogenesis is triggered by reduced oxygen delivery to the tissue, which induces the elaboration by ischemic cells of angiogenic factors such as vascular endothelial growth factor (VEGF). Angiogenesis is characterized by capillary sprouting, endothelial cell migration, proliferation, and luminogenesis to generate new capillaries. Adult vasculogenesis is mediated by the action of circulating cells such as endothelial progenitor cells (EPCs). EPCs are a heterogenous population of cells, largely of hematopoietic lineage, and are characterized by cell-surface antigen markers including CD34, CD133, and VEGF receptor 2 (VEGFR-2). These circulating cells contribute to the expansion of the microvasculature via multiple mechanisms, secretion of paracrine factors playing a prominent role. A small subset of these cells seem to incorporate into the vasculature (inosculation). Arteriogenesis is a positive remodeling of pre-existing collateral channels in the limb. There is little to no flow through these narrow, high resistance channels in healthy individuals. However, when major conduits become severely narrowed or occluded, more flow becomes directed through the collateral channels. Under the influence of vascular shear stress, the diameter of these channels increase. This positive remodeling seems to be because of endothelial factors, as well as infiltrating macrophages. The remodeling process is characterized by dynamic restructuring of the extracellular matrix with degradation and synthesis; vascular smooth muscle cell apoptosis as well as proliferation, which lead to an increased diameter and thickness of the vessel. [Powerpoint File]

Endothelial Cell Metabolism in Normal and Diseased Vasculature

Endothelial Cell Metabolism in Normal and Diseased Vasculature

Guy Eelen, Pauline de Zeeuw, Michael Simons, Peter Carmeliet

Metabolic pathways in tumor vessels and metabolic interactions between cancer and stromal cells. A, Endothelial cells (ECs) in tumor vasculature are presumably characterized by increased glycolysis. B, Metabolic interactions between cancer and stromal cells. 3PG indicates 3-phosphogylcerate; DHAP, dihydroxyacetone phosphate; ER, endoplasmic reticulum; F1,6P2, fructose-1,6-bisphosphate; F2,6P2, fructose-2,6-bisphosphate; G3P, glyceraldehyde-3-phosphate; G6P, glucose-6-phosphate; GLUT, glucose transporter; HIF, hypoxia-inducible factor; IL-8, interleukin-8; LDH, lactate dehydrogenase; NO, nitric oxide; PFK1, phosphofructokinase-1; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3; PHD, prolyl hydroxylase domain; and ROS, reactive oxygen species. [Powerpoint File]

Endothelial Cell Metabolism in Normal and Diseased Vasculature

Endothelial Cell Metabolism in Normal and Diseased Vasculature

Guy Eelen, Pauline de Zeeuw, Michael Simons, Peter Carmeliet

General metabolism in healthy endothelial cells (ECs). Schematic and simplified overview of general EC metabolism. 3PG indicates 3-phosphogylcerate; α-KG, α-ketoglutarate; CoA, coenzyme A; DHAP, dihydroxyacetone phosphate; ETC, electron transport chain; F1,6P2, fructose-1,6-bisphosphate; F2,6P2, fructose-2,6-bisphosphate; F6P, fructose-6-phosphate; FA, fatty acid; G3P, glyceraldehyde-3-phosphate; G6P, glucose-6-phosphate; GLS, glutaminase; GlucN6P, glucosamine-6-phosphate; GSH, reduced glutathione; hCYS, homocysteine; mTHF, 5-methyltetrahydrofolate; NADPH, nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; OAA, oxaloacetate; OXPHOS, oxidative phosphorylation; PFK1, phosphofructokinase-1; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3; R5P, ribose-5-phosphate; ROS, reactive oxygen species; Ru5P, ribulose-5-phosphate; SAM, S-adenosylmethionine; SLC1A5, solute carrier family 1 member 5; TCA, tricarboxylic acid; THF, tetrahydrofolate; and UDP-GlucNAc, uridine diphosphate N-acetylglucosamine. [Poweropint File]

The Right Ventricle in Pulmonary Arterial Hypertension: Disorders of Metabolism, Angiogenesis and Adrenergic Signaling in Right Ventricular Failure

The Right Ventricle in Pulmonary Arterial Hypertension: Disorders of Metabolism, Angiogenesis and Adrenergic Signaling in Right Ventricular Failure

John J. Ryan, Stephen L. Archer

A, Mechanism of impaired glucose oxidation and enhanced glycolysis in right ventricular hypertrophy (RVH). In RVH, activation of various transcription factors, including forkhead box protein O1 (FOXO1), cMyc, and hypoxia-inducible factor 1 α(HIF-1α), upregulates expression of many glycolytic gene. A common finding in RVH is increased pyruvate dehydrogenase kinase (PDK) expression, which inhibits PDH and reduces mitochondrial respiration. PDK activation also occurs in the lung in PAH, although the transcriptional regulation and isoform specificity may differ than those seen in the RV. Dichloroacetate inhibits PDK and thereby promotes glucose oxidation and inhibits glycolysis. Reprinted from Piao et al53 with permission of the publisher. B, The Randle cycle in RVH. The inhibition of β-fatty acid oxidation (FAO) by trimetazidine and ranolazine increases PDH activity and improves glucose oxidation (GO). This reciprocal relationship between GO and FAO is referred to as the Randle cycle. Reprinted from Fang et al78 with permission of the publisher. C, Proposed mechanism of glutaminolysis in RVH. RV ischemia and capillary rarefaction activate cMyc and Max, which increases glutamine uptake and production of α-ketoglutarate (α-KG). α-KG enters Krebs cycle leading to production of malate. Krebs cycle-derived malate generates cytosolic pyruvate, which is converted by lactate dehydrogenase A (LDHA) to lactate. In conditions of high glutaminolysis GO is inhibited. Reprinted from Piao et al26 with permission of the publisher (Illustration Credit: Ben Smith). DON indicates diazo-5-oxo-l-norleucine; ETC, electron transport chain, HK, hexokinase; H2O2, hydrogen peroxide; IMM, inner mitochondrial membrane; OMM, outer mitochondrial membrane; PFK, phosphofructokinase; RAN, ranolazine; and TMZ, trimetazidine. [Powerpoint File]

Angiogenesis and Cardiac Hypertrophy: Maintenance of Cardiac Function and Causative Roles in Heart Failure

Angiogenesis and Cardiac Hypertrophy: Maintenance of Cardiac Function and Causative Roles in Heart Failure

Toru Oka, Hiroshi Akazawa, Atsuhiko T. Naito, Issei Komuro

Hypertrophic responses induce myocardial angiogenesis. Hypertrophic stimuli activate intracellular signaling and transcription factors, such as GATA4 and Hif-1. GATA4 induces the gene expression of structural and contractile proteins, resulting in hypertrophy. Hif-1 is also activated by relative hypoxia/ischemia of the hypertrophied myocardium, and Hif-1 transactivates VEGF gene expression to induce angiogenesis. GSK indicates glycogen synthase kinase; mTOR, mammalian target of rapamycin; and VEGF, vascular endothelial growth factor. [Powerpoint File]

Microvesicles as Cell–Cell Messengers in Cardiovascular Diseases

Microvesicles as Cell–Cell Messengers in Cardiovascular Diseases

Xavier Loyer, Anne-Clémence Vion, Alain Tedgui, Chantal M. Boulanger

Mechanisms involving extracellular vesicles in cell-to-cell communication. Once released, exosomes, microparticles, and apoptotic bodies target recipient cells and are able to transfer information (microRNAs, proteins, etc) by membrane fusion (1), endocytosis (2), or receptor-mediated binding (3). (Illustration credit: Ben Smith). [Powerpoint File]

Heart Failure Compendium: Emerging Paradigms in Cardiomyopathies Associated With Cancer Therapies

Heart Failure Compendium: Emerging Paradigms in Cardiomyopathies Associated With Cancer Therapies

Bonnie Ky, Pimprapa Vejpongsa, Edward T.H. Yeh, Thomas Force, Javid J. Moslehi

Angiogenesis inhibitors (vascular endothelial growth factor [VEGF] signaling pathway [VSP] inhibitors) being tested in human cancer trials. Although these agents are being referred to as VSP inhibitors, drugs such as sunitinib inhibit many other receptor tyrosine kinases, allowing them to be approved for the treatment of other cancers while, at the same time, creating the possibility for a wide range of off-target toxicities. FDA indicates Food and Drug Administration; HIF, hypoxia-inducible factor; PDGF, platelet-derived growth factor; PDGFR, PDGF receptor; TKI, tyrosine kinase inhibitor; and VEGFR, VEGF receptor. (Illustration Credit: Ben Smith.) [Powerpoint File]

Heart Failure Compendium: Emerging Paradigms in Cardiomyopathies Associated With Cancer Therapies

Heart Failure Compendium: Emerging Paradigms in Cardiomyopathies Associated With Cancer Therapies

Bonnie Ky, Pimprapa Vejpongsa, Edward T.H. Yeh, Thomas Force, Javid J. Moslehi

Novel Food and Drug Administration (FDA)–approved and investigational human epidermal growth factor receptor-2 (HER2)–targeted agents being used for the treatment of breast cancer. EGF indicates endothelial growth factor; HB-EGF, heparin-binding EGF; NRG, neuregulins; TGF-α, transforming growth factor α; and TKI, tyrosine kinase inhibitor. (Illustration Credit: Ben Smith.) [Powerpoint File]