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Cited by 147Lymphatic System and DiseasesLymphatic Disorders and TreatmentsLipid metabolism and disorders

Lymphatic vascular integrity is disrupted in type 2 diabetes due to impaired nitric oxide signalling

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Scallan, Joshua P., Hill, Michael A., Davis, Michael J.·2015·Cardiovascular Research
DOI 10.1093/cvr/cvv117PMC PMC4490202
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Abstract

AIMS: Lymphatic vessel dysfunction is an emerging component of metabolic diseases and can lead to tissue lipid accumulation, dyslipidaemia, and oedema. While lymph leakage has been implicated in obesity and hypercholesterolaemia, whether similar lymphatic dysfunction exists in diabetes has not been investigated. METHODS AND RESULTS: To measure the lymphatic integrity of transgenic mice, we developed a new assay that quantifies the solute permeability of murine collecting lymphatic vessels. Compared with age-matched wild-type (WT) controls, the permeability of collecting lymphatics from diabetic, leptin receptor-deficient (db/db) mice was elevated >130-fold. Augmenting nitric oxide (NO) production by suffusion of l-arginine rescued this defect. Using pharmacological tools and eNOS(-/-) mice, we found that NO increased WT lymphatic permeability, but reduced db/db lymphatic permeability. These conflicting actions of NO were reconciled by the finding that phosphodiesterase 3 (PDE3), normally inhibited by NO signalling, was active in db/db lymphatics and inhibition of this enzyme restored barrier function. CONCLUSION: In conclusion, we identified the first lymphatic vascular defect in type 2 diabetes, an enhanced permeability caused by low NO bioavailability. Further, this demonstrates that PDE3 inhibition is required to maintain lymphatic vessel integrity and represents a viable therapeutic target for lymphatic endothelial dysfunction in metabolic disease.

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  • Collecting vessel permeability to albumin is comparable to that of venules.

    “Collecting vessel permeability to albumin has been measured only in a few studies (31–33) and is comparable to that of venules.”

    From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [33]

    Section 3.1 reports measurements of albumin permeability in collecting lymphatics but concludes that lymphatic permeability is higher than that of venular microvessels when measured at the same hydrostatic pressures, rather than comparable. (LLM, conf=0.88)

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  • Lymphatic collecting vessel hyperpermeability has been demonstrated in animal models of type 2 diabetes.

    “For example, lymphatic collecting vessel hyperpermeability has been demonstrated in animal models of type 2 diabetes (33)”

    From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [33]

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Research works printed but not linked: 27

  1. Alitalo K. The lymphatic vasculature in disease. Nat Med 2011;17:1371 -1380.
  2. Stacker SA, Williams SP, Karnezis T, Shayan R, Fox SB, Achen MG. Lymphangiogenesis and lymphatic vessel remodelling in cancer. Nat Rev Cancer 2014;14:159 -172.
  3. Harvey NL, Srinivasan RS, Dillard ME, Johnson NC, Witte MH, Boyd K, Sleeman MW, Oliver G. Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult-onset obesity. Nat Genet 2005;37:1072 -1081.
  4. Wigle JT, Oliver G. Prox1 function is required for the development of the murine lymph- atic system. Cell 1999;98:769-778.
  5. Yang Y, Garcı ´a-Verdugo JM, Soriano-Navarro M, Srinivasan RS, Scallan JP, Singh MK, Epstein JA, Oliver G. Lymphatic endothelial progenitors bud from the cardinal vein and intersomitic vessels in mammalian embryos. Blood 2012;120:2340 -2348.
  6. Sawane M, Kajiya K, Kidoya H, Takagi M, Muramatsu F, Takakura N. Apelin inhibits diet-induced obesity by enhancing lymphatic and blood vessel integrity. Diabetes 2013; 62:1970 -1980.
  7. Lim HY, Rutkowski JM, Helft J, Reddy ST, Swartz MA, Randolph GJ, Angeli V. Hyperch- olesterolemic mice exhibit lymphatic vessel dysfunction and degeneration. Am J Path 2009;175:1328 -1337.
  8. Lim HY, Thiam CH, Yeo KP, Bisoendial R, Hii CS, McGrath KC, Tan KW, Heather A, Alexander JS, Angeli V. Lymphatic vessels are essential for the removal of cholesterol from peripheral tissues by SR-BI-mediated transport of HDL. Cell Metab 2013;17: 671 -684.
  9. Martel C, Li W, Fulp B, Platt AM, Gautier EL, Westerterp M, Bittman R, Tall AR, Chen SH, Thomas MJ, Kreisel D, Swartz MA, Sorci-Thomas MG, Randolph GJ. Lymphatic vascula- ture mediates macrophage reverse cholesterol transport in mice. J Clin Invest 2013;123: 1571 -1579.
  10. Randolph GJ, Miller NE. Lymphatic transport of high-density lipoproteins and chylomi- crons. J Clin Invest 2014;124:929 -935.
  11. Hatakeyama T, Pappas PJ, Hobson RW, Boric MP, Sessa WC, Dura ´n WN. Endothelial nitric oxide synthase regulates microvascular hyperpermeability in vivo. J Physiol 2006; 574:275 -281.
  12. Dura ´n WN, Breslin JW, Sa ´nchez FA. The NO cascade, eNOS location, and microvascu- lar permeability. Cardiovasc Res 2010;87:254 -261.
  13. Kubes P, Granger DN. Nitric oxide modulates microvascular permeability. Am J Physiol 1992;262:H611 -H615.
  14. Kurose I, Wolf R, Grisham MB, Granger DN. Modulation of ischemia/reperfusion- induced microvascular dysfunction by nitric oxide. Circ Res 1994;74:376 -382.
  15. Yuan Y, Granger HJ, Zawieja DC, Chilian WM. Flow modulates coronary venular perme- ability by a nitric oxide-related mechanism. Am J Physiol 1992;263:H641 -H646.
  16. Yuan SY. New insights into eNOS signaling in microvascular permeability. Am J Physiol Heart Circ Physiol 2006;291:H1029 -H1031.
  17. Scallan JP, Davis MJ. Genetic removal of basal nitric oxide enhances contractile activity in isolated murine collecting lymphatic vessels. J Physiol 2013;591:2139 -2156.
  18. Kuo L, Davis MJ, Cannon MS, Chilian WM. Pathophysiological consequences of athero- sclerosis extend into the coronary microcirculation. Restoration of endothelium- dependent responses by L-arginine. Circ Res 1992;70:465 -476.
  19. Pieper GM. Review of alterations in endothelial nitric oxide production in diabetes: pro- tective role of arginine on endothelial dysfunction. Hypertension 1998;31:1047 -1060.
  20. Yuan Y, Granger HJ, Zawieja DC, DeFily DV, Chilian WM. Histamine increases venular permeability via a phospholipase C-NO synthase-guanylate cyclase cascade. Am J Physiol 1993;264:H1734 -H1739.
  21. Breslin JW. ROCK and cAMP promote lymphatic endothelial cell barrier integrity and modulate histamine and thrombin-induced barrier dysfunction. Lymphat Res Biol 2011; 9:3-11.
  22. Curry FR, Adamson RH. Vascular permeability modulation at the cell, microvessel, or whole organ level: towards closing gaps in our knowledge. Cardiovasc Res 2010;87: 218 -229.
  23. Surapisitchat J, Jeon KI, Yan C, Beavo JA. Differential regulation of endothelial cell perme- ability by cGMP via phosphodiesterases 2 and 3. Circ Res 2007;101:811 -818.
  24. Hanson MS, Stephenson AH, Bowles EA, Sprague RS. Insulin inhibits human erythrocyte cAMP accumulation and ATP release: role of phosphodiesterase 3 and phosphoinositide 3-kinase. Exp Biol Med 2010;235:256 -262.
  25. Kitamura T, Kitamura Y, Kuroda S, Hino Y, Ando M, Kotani K, Konishi H, Matsuzaki H, Kikkawa U, Ogawa W, Kasuga M. Insulin-induced phosphorylation and activation of cyclic nucleotide phosphodiesterase 3B by the serine threonine kinase Akt. Mol Cell Biol 1999;19:6286 -6296.
  26. Curry FE, Zeng M, Adamson RH. Thrombin increases permeability only in venules exposed to inflammatory conditions. Am J Physiol Heart Circ Physiol 2003;285: H2446 -H2453.
  27. Kimura T, Hamazaki TS, Sugaya M, Fukuda S, Chan T, Tamura-Nakano M, Sato S, Okochi H. Cilostazol improves lymphatic function by inducing proliferation and stabiliza- tion of lymphatic endothelial cells. J Dermatol Sci 2014;74:150 -158.

Cited by

Sorted by citations

Authors
Scallan, J. P., Hill, M. A., & Davis, M. J.
Affiliations
University of Missouri (US)
Corresponding author
Davis, Michael J.
ORCID
Venue
Cardiovascular Research
Publisher
Oxford University Press (OUP)
Published
2015-04-07
Volume
107
Issue
1
Pages
89-97
ISSN
  • 0008-6363 (ISSN-L)
  • 1755-3245
DOI
10.1093/cvr/cvv117
PMC
PMC4490202
OpenAlex
W1970920203
Cited by
147
References
4
Citations by year
2026: 13 · 2025: 10 · 2024: 14 · 2023: 18 · 2022: 18 · 2021: 14 · 2020: 17 · 2019: 9 · 2018: 10 · 2017: 10 · 2016: 12 · 2015: 1
FWCI
4.80
Type
journal article
Language
en
Open access
Locations
  • Cardiovascular Research (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (HL 095486)
  • National Heart, Lung, and Blood Institute (R01HL085119, R01HL120867, HL095486, P01HL095486, K99HL124142, R01HL089784)
Topics
  • Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
  • Health Sciences › Medicine › Surgery › Lymphatic Disorders and Treatments
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Keywords
type 2 diabetes, nitric oxide signaling, lymphatic permeability, phosphodiesterase 3, endothelial nitric oxide synthase, db/db mice, leptin receptor deficiency, L-arginine, metabolic disorders
MeSH terms
Animals, Arginine, Capillary Permeability, Diabetes Mellitus, Type 2, Female, Male, Mice, Inbred C57BL, Nitric Oxide, Signal Transduction, Lymphatic Vessels, Mice, Phosphodiesterase 3 Inhibitors

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