Lymphatic Vessel Remodeling in the Hearts of Ang II-Treated Obese db/db Mice as an Integral Component of Cardiac Remodeling
Source abstract
Abstract
Cardiac lymphatic vessels (LyVs) are suggested to be important players in cardiovascular disease-associated myocardial remodeling. However, there is a gap in the knowledge of whether LyV remodeling is an integral component of cardiac remodeling, especially in obesity associated with other comorbidities, including increased levels of circulating angiotensin II (Ang II). We studied the structural alterations in the myocardium and LyVs in Ang II-treated db/db mice compared with db/db mice and Ang II-treated wild-type mice with histopathological imaging methods, confocal microscopy, ultrastructural morphology, and morphometric analysis. We demonstrated that Ang II-treated db/db mice exhibited significantly increased fibrosis, cardiomyocyte hypertrophy, and local edema compared with untreated db/db mice; however, the cardiomyocyte hypertrophy was similar to that in Ang II-treated control mice. The decreased density of the LyVs and their wall shape alterations, with disorganized anchoring filaments, widened junctional gaps, decreased numbers of cytoplasmic vesicles indicative of a leaky phenotype, and increased basement membrane (BM) thickness, were observed in Ang II-treated db/db mice compared with Ang II-treated controls. Our findings revealed a structural basis for intensive LyV remodeling in association with cardiac remodeling in obesity.
Source: crossref · Quality: baseline
Research context
OpenAlex topics: Cardiovascular Disease and Adiposity · Heart Rate Variability and Autonomic Control · Cardiovascular Function and Risk Factors
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
Department of Pathology, Medical University of Warsaw, 02-091 Warsaw, Poland
Department of Histology and Embryology, Center for Biostructure, Medical University of Warsaw, 02-004 Warsaw, Poland
Department of Experimental and Clinical Physiology, Medical University of Warsaw, 02-091 Warsaw, Poland
Postgraduate School of Molecular Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland
Department of General, Transplant and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland
Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland
School of Cardiovascular and Metabolic Medicine & Sciences, King’s College London, London SE5 8AF, UK
Division of Histology and Embryology, Department of Morphological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, 02-776 Warsaw, Poland
Laboratory of Advanced Microscopy Techniques, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland
Department of Clinical and Descriptive Anatomy, Center for Biostructure, Medical University of Warsaw, 02-004 Warsaw, Poland
Electron Microscopy Research Unit, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland
Funding
NCBR · National Science Center · Ministry of Science and Higher Education
References (100+)
Show source-provided references
1. The metabolic syndrome: More than the sum of its parts?10.1161/01.CIR.0000088846.10655.E0 ↗
2. Harmonizing the metabolic syndrome: A joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity10.1161/CIRCULATIONAHA.109.192644 ↗
3. A comprehensive definition for metabolic syndrome10.1242/dmm.001180 ↗
4. Metabolic syndrome update10.1016/j.tcm.2015.10.004 ↗
5. Lymphatics in Cardiovascular Physiology10.1101/cshperspect.a041173 ↗
6. Lymphatic vascular integrity is disrupted in type 2 diabetes due to impaired nitric oxide signalling10.1093/cvr/cvv117 ↗
7. Epsin deficiency promotes lymphangiogenesis through regulation of VEGFR3 degradation in diabetes10.1172/JCI96063 ↗
8. Visceral obesity and insulin resistance associate with CD36 deletion in lymphatic endothelial cells10.1038/s41467-021-23808-3 ↗
9. Blunted flow-mediated responses and diminished nitric oxide synthase expression in lymphatic thoracic ducts of a rat model of metabolic syndrome10.1152/ajpheart.00664.2015 ↗
10. Obesity-induced lymphatic dysfunction is reversible with weight loss10.1113/JP273061 ↗
11. Vascular Endothelial Growth Factor-D (VEGF-D) Overexpression and Lymphatic Expansion in Murine Adipose Tissue Improves Metabolism in Obesity10.1016/j.ajpath.2018.12.008 ↗
12. Chakraborty, A., Scogin, C.K., Rizwan, K., Morley, T.S., and Rutkowski, J.M. (2020). Characterizing Lymphangiogenesis and Concurrent Inflammation in Adipose Tissue in Response to VEGF-D. Front. Physiol., 11.10.3389/fphys.2020.00363 ↗
13. CXCL1-CXCR2 axis mediates angiotensin II-induced cardiac hypertrophy and remodelling through regulation of monocyte infiltration10.1093/eurheartj/ehy085 ↗
14. Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology10.1152/physrev.00038.2017 ↗
15. Lin, Q.Y., Bai, J., Liu, J.Q., and Li, H.H. (2020). Angiotensin II Stimulates the Proliferation and Migration of Lymphatic Endothelial Cells Through Angiotensin Type 1 Receptors. Front. Physiol., 11.10.3389/fphys.2020.560170 ↗
16. Angiotensin II Induces Cardiac Edema and Hypertrophic Remodeling through Lymphatic-Dependent Mechanisms10.1155/2022/5044046 ↗
17. The role of lymphatic vessels in the heart
18. Cardiac lymphatics in health and disease10.1038/s41569-018-0087-8 ↗
19. The evolving cardiac lymphatic vasculature in development, repair and regeneration10.1038/s41569-020-00489-x ↗
20. Lymphangiogenesis: A new strategy for heart disease treatment (Review)10.3892/ijmm.2024.5359 ↗
21. Cardiac Lymphangiogenesis in CVDs10.1161/ATVBAHA.123.319572 ↗
22. Evidence for a second valve system in lymphatics: Endothelial microvalves10.1096/fj.01-0067com ↗
23. Lymphatic Vessel Network Structure and Physiology10.1002/cphy.c180015 ↗
24. Lymphatics in Cardiovascular Disease10.1161/ATVBAHA.120.314735 ↗
25. Null, M., Arbor, T.C., and Agarwal, M. (2023). Anatomy, Lymphatic System, StatPearls Publishing.
26. A model for mechanics of primary lymphatic valves10.1115/1.1568128 ↗
27. Functionally specialized junctions between endothelial cells of lymphatic vessels10.1084/jem.20062596 ↗
28. Primary and secondary lymphatic valve development: Molecular, functional and mechanical insights10.1016/j.mvr.2014.07.008 ↗
29. Transcellular Pathways in Lymphatic Endothelial Cells Regulate Changes in Solute Transport by Fluid Stress10.1161/CIRCRESAHA.116.309828 ↗
30. Jannaway, M., and Scallan, J.P. (2021). VE-Cadherin and Vesicles Differentially Regulate Lymphatic Vascular Permeability to Solutes of Various Sizes. Front. Physiol., 12.10.3389/fphys.2021.687563 ↗
31. Apelin inhibits diet-induced obesity by enhancing lymphatic and blood vessel integrity10.2337/db12-0604 ↗
32. Obesity increases inflammation and impairs lymphatic function in a mouse model of lymphedema10.1152/ajpheart.00244.2014 ↗
33. Crosstalk between Adipose and Lymphatics in Health and Disease10.1210/endocr/bqab224 ↗
34. Hypercholesterolemic mice exhibit lymphatic vessel dysfunction and degeneration10.2353/ajpath.2009.080963 ↗
35. Emilin1 deficiency causes structural and functional defects of lymphatic vasculature10.1128/MCB.02062-07 ↗
36. EMILIN1/alpha9beta1 integrin interaction is crucial in lymphatic valve formation and maintenance10.1128/MCB.00872-13 ↗
37. A human initial lymphatic chip reveals distinct mechanisms of primary lymphatic valve dysfunction in acute and chronic inflammation10.1039/D3LC00486D ↗
38. Ultrastructure changes of cardiac lymphatics during cardiac fibrosis in hypertensive rats10.1002/ar.20943 ↗
39. Biomechanical control of lymphatic vessel physiology and functions10.1038/s41423-023-01042-9 ↗
40. Role of Cardiac Lymphatics in Myocardial Edema and Fibrosis: JACC Review Topic of the Week10.1016/j.jacc.2020.05.076 ↗
41. Microvascular and lymphatic dysfunction in HFpEF and its associated comorbidities10.1007/s00395-020-0798-y ↗
42. Recommendations for blood pressure measurement in humans and experimental animals. Part 2: Blood pressure measurement in experimental animals: A statement for professionals from the subcommittee of professional and public education of the American Heart Association council on high blood pressure research10.1161/01.HYP.0000150857.39919.cb ↗
43. Use of tibial length to quantify cardiac hypertrophy: Application in the aging rat
44. A formaldehyde-glutaraldehyde fixative of high osmolality for use in electron microscopy
45. Cardiac mouse lymphatics: Developmental and anatomical update10.1002/ar.22912 ↗
46. Picrosirius red staining of cardiac muscle following phosphomolybdic acid treatment10.3109/10520298709107961 ↗
47. A modified Verhoeff’s elastin histochemical stain to enable pulmonary arterial hypertension model characterization
48. Vasculogenic and hematopoietic cellular progenitors are scattered within the prenatal mouse heart10.1007/s00418-014-1269-z ↗
49. Myocardial capillary supply is limited in hypertrophic cardiomyopathy: A morphological analysis10.1016/j.ijcard.2007.04.003 ↗
50. The Ebb and Flow of Cardiac Lymphatics: A Tidal Wave of New Discoveries10.1152/physrev.00052.2021 ↗
51. Obesity-related hypertension: A review of pathophysiology, management, and the role of metabolic surgery10.21037/gs.2019.12.03 ↗
52. van Bilsen, M., Daniels, A., Brouwers, O., Janssen, B.J., Derks, W.J., Brouns, A.E., Munts, C., Schalkwijk, C.G., van der Vusse, G.J., and van Nieuwenhoven, F.A. (2014). Hypertension is a conditional factor for the development of cardiac hypertrophy in type 2 diabetic mice. PLoS ONE, 9.10.1371/journal.pone.0085078 ↗
53. Characterization of a mouse model of obesity-related fibrotic cardiomyopathy that recapitulates features of human heart failure with preserved ejection fraction10.1152/ajpheart.00238.2018 ↗
54. Metabolic syndrome: Focus on dyslipidemia10.1038/oby.2006.281 ↗
55. Characterization of plasma lipids in genetically obese mice: The mutants obese, diabetes, fat, tubby, and lethal yellow10.1016/0026-0495(94)90194-5 ↗
56. Triglyceride Metabolism in the Liver
57. Chronic ANG II infusion increases plasma triglyceride level by stimulating hepatic triglyceride production in rats10.1152/ajpendo.00199.2004 ↗
58. Olmesartan medoxomil, an angiotensin II receptor blocker ameliorates insulin resistance and decreases triglyceride production in fructose-fed rats10.1291/hypres.27.293 ↗
59. Angiotensin II type 1 receptor blocker ameliorates overproduction and accumulation of triglyceride in the liver of Zucker fatty rats10.1152/ajpendo.00090.2004 ↗
60. Diabetic hypertensive leptin receptor-deficient db/db mice develop cardioregulatory autonomic dysfunction10.1161/HYPERTENSIONAHA.108.124776 ↗
61. Obesity and heart failure: Epidemiology, pathophysiology, clinical manifestations, and management
62. Impact of obesity and weight loss on cardiac performance and morphology in adults10.1016/j.pcad.2013.09.003 ↗
63. Obesity and Heart Failure: Focus on the Obesity Paradox10.1016/j.mayocp.2016.11.001 ↗
64. Angiotensin II induces inflammation leading to cardiac remodeling10.2741/3923 ↗
65. Angiotensin II and inflammation: The effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockade10.1038/sj.jhh.1002101 ↗
66. Regulation of myocardial fibrillar collagen by angiotensin II. A role in hypertensive heart disease?10.1006/jmcc.2002.2081 ↗
67. Angiotensin II-induced cardiomyocyte hypertrophy in vitro is TAK1-dependent and Smad2/3-independent10.1038/hr.2011.196 ↗
68. Thomas, T.P., and Grisanti, L.A. (2020). The Dynamic Interplay Between Cardiac Inflammation and Fibrosis. Front. Physiol., 11.10.3389/fphys.2020.529075 ↗
69. Nguyen, D.V., Shaw, L.C., and Grant, M.B. (2012). Inflammation in the pathogenesis of microvascular complications in diabetes. Front. Endocrinol., 3.10.3389/fendo.2012.00170 ↗
70. Metabolic syndrome, insulin resistance, and roles of inflammation--mechanisms and therapeutic targets10.1161/ATVBAHA.111.241869 ↗
71. Angiotensin-(1-7) administration benefits cardiac, renal and progenitor cell function in db/db mice10.1111/bph.13225 ↗
72. Elevated lymphatic vessel density measured by Lyve-1 expression in areas of replacement fibrosis in the ventricular septum of patients with hypertrophic obstructive cardiomyopathy (HOCM)10.1007/s00380-019-01463-5 ↗
73. Disruption of leptin signaling contributes to cardiac hypertrophy independently of body weight in mice10.1161/01.CIR.0000083716.82622.FD ↗
74. Leptin signaling and obesity: Cardiovascular consequences10.1161/CIRCRESAHA.107.156596 ↗
75. Evidence that the diabetes gene encodes the leptin receptor: Identification of a mutation in the leptin receptor gene in db/db mice10.1016/S0092-8674(00)81294-5 ↗
76. Involvement of nitric oxide in endothelium-dependent arterial relaxation by leptin10.1006/bbrc.2000.3005 ↗
77. Reduction of obesity, as induced by leptin, reverses endothelial dysfunction in obese (Lep(ob)) mice10.1152/jappl.2000.89.6.2382 ↗
78. Mechanisms of cardiac fibrosis in hypertension10.1111/j.1524-6175.2007.06626.x ↗
79. Interstitial fluid flow and cyclic strain differentially regulate cardiac fibroblast activation via AT1R and TGF-β110.1016/j.yexcr.2011.10.008 ↗
80. The relationship between myocardial extracellular matrix remodeling and ventricular function10.1016/j.ejcts.2006.07.006 ↗
81. Myocardial stiffness is determined by ventricular fibrosis, but not by compensatory or excessive hypertrophy in hypertensive heart10.1016/S0008-6363(02)00341-3 ↗
82. The cardiac lymphatics10.1097/00000658-197006010-00011 ↗
83. The cardiac lymphatics10.1016/S0003-4975(10)65339-8 ↗
84. Reduced Lymphatic Reserve in Heart Failure with Preserved Ejection Fraction10.1016/j.jacc.2020.10.022 ↗
85. Obesity but not high-fat diet impairs lymphatic function10.1038/ijo.2016.96 ↗
86. Lymphangiogenic therapy prevents cardiac dysfunction by ameliorating inflammation and hypertension10.7554/eLife.58376 ↗
87. A directed network analysis of the cardiome identifies molecular pathways contributing to the development of HFpEF10.1016/j.yjmcc.2020.05.008 ↗
88. Extracellular matrix molecules associated with lymphatic vessels in health and disease
89. TGF-β signaling in fibrosis10.3109/08977194.2011.595714 ↗
90. Homeostatic maintenance of the lymphatic vasculature10.1016/j.molmed.2021.07.003 ↗
91. Structure and biosynthesis of basement membranes10.1016/B978-0-12-363706-2.50008-8 ↗
92. Basement membrane collagens and disease mechanisms10.1042/EBC20180071 ↗
93. Possible contribution of basement membrane to the structural rigidity of blood capillaries10.1016/0026-2862(75)90084-9 ↗
94. Collagen IV is essential for basement membrane stability but dispensable for initiation of its assembly during early development10.1242/dev.01037 ↗
95. The vascular niche and its basement membrane10.1016/j.tcb.2006.11.005 ↗
96. Pathological MAPK activation-mediated lymphatic basement membrane disruption causes lymphangiectasia that is treatable with ravoxertinib10.1172/jci.insight.153033 ↗
97. Signaling pathways in vascular function and hypertension: Molecular mechanisms and therapeutic interventions10.1038/s41392-023-01430-7 ↗
98. Rethinking glomerular basement membrane thickening in diabetic nephropathy: Adaptive or pathogenic?10.1152/ajprenal.00313.2016 ↗
99. The primary valves in the initial lymphatics during inflammation10.1089/lrb.2007.5102 ↗
100. Specific adhesion molecules bind anchoring filaments and endothelial cells in human skin initial lymphatics