Posts in Category: Hypertension

Gut Microbiota in Cardiovascular Health and Disease

Gut Microbiota in Cardiovascular Health and Disease

W.H. Wilson Tang, Takeshi Kitai, Stanley L. Hazen

Gut microbiota and possible molecular pathways linked to cardiovascular and cardiometabolic diseases. BAT indicates brown adipose tissue; FXR, farnesoid X receptor; GLP, glucagon-like peptide; GPR, G-protein–coupled receptor; LPS, lipopolysaccharide; PYY, peptide YY; TLR, toll-like receptor; TMA, trimethylamine; and TMAO, trimethylamine N-oxide. [Powerpoint File]

Purinergic Signaling in the Cardiovascular System

Purinergic Signaling in the Cardiovascular System

Geoffrey Burnstock

Central vagal cardiocardiac reflex triggered by ATP.230 Illustration Credit: Ben Smith. [Powerpoint File]

Purinergic Signaling in the Cardiovascular System

Purinergic Signaling in the Cardiovascular System

Geoffrey Burnstock

Three P2 receptor subtypes, P2X1, P2Y1, and P2Y12, are involved in ADP-induced platelet activation. Clopidogrel is a P2Y12 receptor blocker that inhibits platelet aggregation and is in highly successful use for the treatment of thrombosis and stroke. A P2Y1 receptor antagonist, MRS 2500, inhibits shape change.234 Illustration Credit: Ben Smith. [Powerpoint FIle]

Treatment of Obesity: Weight Loss and Bariatric Surgery

Treatment of Obesity: Weight Loss and Bariatric Surgery

Bruce M. Wolfe, Elizaveta Kvach, Robert H. Eckel

Diagram of surgical options. Image credit: Walter Pories, MD, FACS. [Powerpoint File]

Brain–Gut–Bone Marrow Axis: Implications for Hypertension and Related Therapeutics

Brain–Gut–Bone Marrow Axis: Implications for Hypertension and Related Therapeutics

Monica M. Santisteban, Seungbum Kim, Carl J. Pepine, Mohan K. Raizada

Brain–gut–bone marrow (BM) axis. Increases in prohypertensive stimuli, such as angiotensin II (Ang II), enhance neuronal activity and trigger neuroinflammatory pathways in cardioregulatory brain centers to result in sympathoexcitation. Sympathetic activity to the BM induces mobilization of hematopoietic stem cells, and Ang II stimulates their differentiation into inflammatory cells. These cells may then migrate to the brain to become microglia/macrophages and propagate neuroinflammation, as well as to the gut to contribute to low-grade intestinal inflammation. Sympathetic activity to the gut could modulate motility as well as the local immune response. Finally, the low-grade inflammation of the gut coupled with alterations in the gut microbiota may result in bacterial metabolites entering circulation, where they could negatively affect both brain neuronal activity as well as the BM immune cells. This triangular interaction may play an important role in perpetuating the progression of hypertension and may be critical in the establishment of resistant hypertension. CMP indicates common myeloid progenitor; HTN, hypertension; PSA, parasympathetic nerve activity; PVN, paraventricular nucleus; and SNA, sympathetic nerve activity. [Powerpoint File]

Lymphatic System in Cardiovascular Medicine

Lymphatic System in Cardiovascular Medicine

Aleksanteri Aspelund, Marius R. Robciuc, Sinem Karaman, Taija Makinen, Kari Alitalo

Lymphatic vessel role in fat absorption and adipose deposition. A, VEGFC is expressed in a subset of smooth muscle fibers in the intestinal villi and in the circular smooth muscle layer of the intestinal wall, as well as in the arterial SMCs. Vegfc deletion induces intestinal lymphatic vessel atrophy, reducing lipid absorption by the lacteal vessels and thus diet-induced obesity.149 VEGFC may also regulate the contraction of lacteal-associated smooth muscle fibers, which have an important role in lipid absorption.38,150 B, Lymph leakage in Prox1+/- mice leads to increased adipogenesis.43 [Powerpoint File]

Lymphatic System in Cardiovascular Medicine

Lymphatic System in Cardiovascular Medicine

Aleksanteri Aspelund, Marius R. Robciuc, Sinem Karaman, Taija Makinen, Kari Alitalo

Organization of the lymphatic vascular tree. A, In overview, the unidirectional lymphatic vascular system consists of (1) lymphatic capillaries, (2) collecting lymphatic vessels, (3) lymph nodes, and (4) the thoracic duct and right lymphatic trunk. B, Lymphatic capillaries absorb interstitial solutes, macromolecules, and immune cells that extravasate from the blood vascular system. Lymph formation is facilitated by the discontinuous basement membrane (red dashed line), and button-like endothelial junctions allow passive paracellular flow for lymph formation. Adapted from Baluk et al17 with permission. C, Collecting lymphatic vessels contain zipper-like junctions, lymphatic valves, and contractile smooth muscle cells (SMCs) that enable the unidirectional propulsion of lymph. D, Organization of the lymph node with afferent lymphatic vessels and a single efferent lymphatic vessel. E, Lymph drains into venous circulation through 4 distinct lymphovenous valves located where the internal jugular vein (IJV) and external jugular vein (EJV) drain into the subclavian vein (SCV). [Powerpoint File]

Lymphatic System in Cardiovascular Medicine

Lymphatic System in Cardiovascular Medicine

Aleksanteri Aspelund, Marius R. Robciuc, Sinem Karaman, Taija Makinen, Kari Alitalo

Development of the lymphatic vascular tree. A, The common cardinal vein (CCV) at E9.0. B, Specification of lymphatic endothelial cells (LECs) at E9.5, identified by PROX1 expression in the CCV, in the intersomitic veins and in the superficial plexus. C, Budding of initial LECs (iLECs) from the CCV at E10 to E10.25. D, Formation of the lymph sacs, comprising the primordial thoracic duct (pTD) and primordial longitudinal lymphatic vessel (PLLV) between E10.5 and E11.5. E, Two mechanisms of expansion of the lymphatic vascular tree: lymphangiogenesis and lymphvasculogenesis. F, Lymphatic vessel maturation and remodeling from E14.5 onward: recruitment of smooth muscle cell (SMC) coverage and valve formation. Panels A–D adapted from Hägerling et al59 with permission. Panel E derived from Stanczuk et al.55 BEC indicates blood endothelial cell. [Powerpoint File]

Lymphatic System in Cardiovascular Medicine

Lymphatic System in Cardiovascular Medicine

Aleksanteri Aspelund, Marius R. Robciuc, Sinem Karaman, Taija Makinen, Kari Alitalo

Mechanisms of VEGFC activation by CCBE1 and ADAMTS3. Paracrine CCBE1 secretion at sites of lymphatic vessel growth promotes the proteolytic cleavage of the poorly active 29/31 kDa form of VEGFC (pro-VEGFC) by the disintegrin/metalloprotease ADAMTS3 and possibly by other proteases. This results in the formation of a mature 21/23 kDa form of VEGFC that can fully activate VEGFR3. Although CCBE1 binds to extracellular matrix (ECM), most of the VEGFC cleavage may occur on lymphatic endothelial cell (LEC) surface. The phenotypes of the related gene-targeted mice are indicated. Image derived from Jeltsch et al.85 WT indicates wild-type. [Powerpoint File]

Lymphatic System in Cardiovascular Medicine

Lymphatic System in Cardiovascular Medicine

Aleksanteri Aspelund, Marius R. Robciuc, Sinem Karaman, Taija Makinen, Kari Alitalo

Lymphatic vessel role in cholesterol metabolism, atherosclerosis, and myocardial infarction. A, Whole mount staining of adult heart showing epicardial lymphatic vessels stained for VEGFR3 and LYVE1. B, Schematic overview of the heart with myocardial infarction caused by the occlusion of the atherosclerotic coronary artery. Proliferation of lymphatic vessels occurs in the affected area. C, Cross section of an atherosclerotic coronary artery and an adventitial lymphatic vessel. D, Hypothetical model for the role of lymphatic vessels in high-density lipoprotein (HDL)–mediated cholesterol removal from atherosclerotic plaques. Plasma-derived HDL enters the atherosclerotic plaque, interacts with ABCA1 or ABCG1 translocases at the plasma membrane of a cholesterol-loaded macrophage (foam cell, enlarged), binds cholesterol, and may exit via lymphatic vessels located in the vicinity of the coronary artery. Possible roles of VEGFC in atherosclerosis and myocardial infarction are highlighted with the bullet points. [Powerpoint File]

The Genetic Basis of Peripheral Arterial Disease: Current Knowledge, Challenges, and Future Directions

The Genetic Basis of Peripheral Arterial Disease: Current Knowledge, Challenges, and Future Directions

Iftikhar J. Kullo, Nicholas J. Leeper

Arterial pathology in atherosclerotic, inflammatory, and nonatherosclerotic noninflammatory arteriopathies. Atherosclerosis is characterized by plaques with varying amounts of inflammatory cells, lipid deposition, fibrosis, calcification, cellular necrosis, smooth muscle proliferation and necrosis, disruption of internal elastic lamina. Inflammatory arterial diseases are characterized by marked inflammatory cell infiltration and in the case of large vessel vasculitis, by giant cell formation. Features of noninflammatory nonatherosclerotic arterial disease vary. In fibromuscular dysplasia, the prominent features are excessive fibroblasts, deposition of increased amounts of extra cellular matrix, and relative paucity of inflammatory cells. [Powerpoint File]

Role of Mechanotransduction in Vascular Biology: Focus on Thoracic Aortic Aneurysms and Dissections

Role of Mechanotransduction in Vascular Biology: Focus on Thoracic Aortic Aneurysms and Dissections

Jay D. Humphrey, Martin A. Schwartz, George Tellides, Dianna M. Milewicz

Thoracic aortic aneurysms and dissections (TAADs) manifest clinically at the macro (tissue)-level but result from mechanisms at the micro (molecular)-level. Shown are aortic structure and relevant mechanical stresses (see text) that result from hemodynamic loading. The stressed wall consists of 3 layers (intima, media, and adventitia) populated, respectively, by 3 cell types (endothelial, smooth muscle, and fibroblasts). Medial lamellar units consist of paired concentric deliminating elastic laminae (elastin plus microfibrils), with associated smooth muscle cells, collagens, and glycosaminoglycans. A unique contractile-elastic unit consists of colinear extracellular microfibrils connecting through heterodimeric transmembrane complexes (integrins) with intracellular actomyosin filaments to create load-bearing or sensing functions. Linker proteins within the focal adhesion have structural or signaling roles. ECM indicates extracellular matrix. [Powerpoint File]

Genetic and Molecular Aspects of Hypertension

Genetic and Molecular Aspects of Hypertension

Sandosh Padmanabhan, Mark Caulfield, Anna F. Dominiczak

Molecular pathways affecting sodium transport involving Cullin 3 (CUL3), Kelch-like 3 (KLHL3), and Uromodulin (UMOD). Cul3 E3 ligase complex can regulate WNK4 function. The Cul3 ubiquitin ligase activity is promoted by its binding to Nedd8, and Cul3 can interact with KLHL3 and ubiquitylates WNK4. The regulation of Cul3 neddylation and Cul3 activity could be considered as a new form of modulation of WNK4 pathway in distal convoluted tubular and collecting duct cells. Mutations in Cul3 or KLHL3 can lead to hypertension by impaired interaction with and ubiquitination of WNK4 and is proposed that any deregulation in its function could lead to hypertension. Molecular context of UMOD in the thick ascending limb of loop of Henle cells. UAKD mutations are restricted to exons 3 and 4. Genome-wide association study (GWAS) single nucleotide polymorphisms (SNPs) for hypertension and chronic kidney disease are located in the promoter end of the gene and variants with reduced UMOD expression can result in a shift to the left of the pressure-natriuresis curve. The region of linkage disequilibrium (LD) around the GWAS SNP is longer for Europeans, but much smaller among those of African and East Asian ancestries. The mechanism of UMOD effect on glomerular filtration rate is not clear and likely involves tubuloglomerular feedback. CEU, European ancestry; CD, collecting duct; ClC-Ka, chloride channel protein class Ka; Clc-Kb, chloride channel protein class Kb; DCT, distal convoluted tubule; E.R., endoplasmic reticulum; GPI, glycosylphosphatidylinositol; JPT, Japanese ancestry; MD, macula densa; NKCC2, Na+ K+ 2Cl− cotransporter 2; PCT, proximal convoluted tubule; ROMK, renal outer medullary potassium channel; TAL, thick ascending limb of loop of Henle; UAKD, uromodulin associated kidney disease; and YRI, African ancestry (Illustration credit: Ben Smith). [Powerpoint File]

Hypertension: Renin–Angiotensin–Aldosterone System Alterations

Hypertension: Renin–Angiotensin–Aldosterone System Alterations

Luuk te Riet, Joep H.M. van Esch, Anton J.M. Roks, Anton H. van den Meiracker, A.H. Jan Danser

Circulating versus tissue renin–angiotensin (Ang) system. Circulating renin is kidney-derived, and circulating angiotensinogen originates in the liver. Angiotensin-converting enzyme (ACE) is located on endothelial cells. Ang II generated in the circulation will diffuse to tissues to bind to its main receptor (the Ang II type 1 receptor, AT1R) to exert effects. In addition, circulating renin and angiotensinogen might also diffuse to tissue sites (eg, the interstitial space) and generate, with the help of tissue ACE, Ang II locally. In a limited number of tissues, renin’s precursor prorenin is produced locally. To what degree such prorenin, for example, following its conversion to renin, contributes to local angiotensin production remains unknown. Although local production has also been claimed for angiotensinogen, in particular in the kidney, current evidence does not support a functional role for kidney-derived angiotensinogen because the renal Ang II levels in renal angiotensinogen knockout (KO) mice are identical to those in wild-type mice.11 Locally generated Ang II rapidly binds to AT1 and AT2 receptors, the former being followed by internalization. This explains the intracellular presence of Ang II, as well as the high tissue levels of Ang II in high AT1 receptor-density organs like the adrenal (Illustrated Credit: Ben Smith). [Powerpoint File]

The Structural Factor of Hypertension: Large and Small Artery Alterations

The Structural Factor of Hypertension: Large and Small Artery Alterations

Stéphane Laurent, Pierre Boutouyrie

Schematic representation of the role of arterial stiffness in assuming blood flow through the peripheral circulation (Reprinted from Briet et al65 with permission). [Powerpoint File]