10.4081/btvb.2023.99
The Lefoulon Delalande Foundation awarded its 2023 Scientific Grand Prize to Kari Alitalo from the University of Helsinki and the Wihuri Research Institute in Finland, and to Susan Quaggin from the Feinberg School of Medicine at NorthWestern University in Chicago, USA. The 600,000-euro prize is awarded annually for researchers who significantly contributed to cardiovascular physiology, biology or medicine, and the 2023 edition was equally shared between the two laureates....
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Bleeding, Thrombosis and Vascular Biology
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The Lefoulon Delalande Foundation honors the lymphatic vascular system
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Thomson BR, Souma T, Tompson SW, et al. Angiopoietin-1 is required for Schlemm's canal development in mice and humans. J Clin Invest 2017;127:4421-36.
The Lefoulon Delalande Foundation honors the lymphatic vascular system
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                                                                                                             INVITED EDITORIAL

The Lefoulon Delalande Foundation honors the lymphatic vascular
system
Anne Eichmann

Cardiovascular Research Center, Department of Cellular and Molecular Physiology, Yale University School of Medicine, New
Haven, CT, USA; INSERM U970, Paris Cardiovascular Research Center, Paris, France




    The Lefoulon Delalande Foundation awarded its 2023 Sci-                  vascular system in human health and disease. Lymphatic vascu-
entific Grand Prize to Kari Alitalo from the University of                   lature constitutes the draining arm of the cardiovascular system
Helsinki and the Wihuri Research Institute in Finland, and to                (Figure 1A). As blood pressure drives plasma fluid from circu-
Susan Quaggin from the Feinberg School of Medicine at North-                 lating blood across capillaries into the body tissues, it bathes the
western University in Chicago, USA. The 600 000-euro prize is                tissues as interstitial fluid, carrying nutrients to the cells and col-




                                                                                                ly
awarded annually for researchers who significantly contributed               lecting waste products, infectious agents, and damaged cells.
to cardiovascular physiology, biology or medicine, and the 2023              Lymphatics are responsible for removing interstitial fluid along




                                                                                        on
edition was equally shared between the two laureates.                        with macromolecules and immune cells from body tissues, and
    The 2023 Prize highlights the importance of the lymphatic                they also control lipid absorption in the gut. The mixture of flu-
                                                                             ids, lipids and waste products is called lymph once it is taken up




                                                                                  e
                                                                             by lymphatic capillaries in various tissues. Lymphatic capillaries

  Correspondence: Anne Eichmann, Cardiovascular Research Center
  and Department of Cellular and Molecular Physiology, Yale Uni-
                                                                            us
                                                                             take up lymph via specialized open junctions that facilitate entry.
                                                                             Lymphatic capillaries then coalesce into progressively larger and
                                                                             impermeable collecting vessels, which transport lymph back to
                                                                            al
  versity School of Medicine, New Haven, CT 06510-3221, USA;                 the systemic circulation via large lymph ducts that merge with
  INSERM U970, Paris Cardiovascular Research Center, 75015                   the subclavian veins (Figure 1A). Along the way, lymph passes
                                                         ci

  Paris, France.                                                             through numerous lymph nodes, which filter out unwanted ma-
  E-mail: anne.eichmann@yale.edu
                                                       er


                                                                             terials such as bacteria and damaged cells, hence lymphatics di-
  Citation: Eichmann A. The Lefoulon Delalande Foundation honors             rectly communicate with the immune system to fight infections
                                                      m



  the lymphatic vascular system. Bleeding, Thrombosis, and Vascu-            (Figure 1A and B).1-3
  lar Biology 2023;2:99.                                                          Given the importance of a proper tissue drainage system,
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                                                                             lymphatic dysfunction is intimately associated with diseases.
  Key words: Lefoulon Delalande Foundation, lymphatic vascular               Genetic defects that prevent lymphatic vessels from forming
  system, editorial.                                                         properly lead to lymphedema, which is a disabling and disfig-
                                    -c




  Conflict of interest: the author declares no potential conflict of in-     uring condition associated with accumulation of protein-rich
  terest.                                                                    fluid and tissue swelling (Figure 1C). Lymphedema can also be
                           on




                                                                             acquired, notably in breast cancer patients upon surgical removal
  Funding: none.                                                             of lymph nodes. The lymph node removal is performed to pre-
                                                                             vent the metastatic spread of cancer cells, which also occurs
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  Acknowledgments: the author is grateful to Professor Mario                 through lymphatic vessels (Figure 1D). In addition to lym-
  Colucci, Aldo Moro University, Bari, Italy for the original design
  of the scheme shown in Figure 1.                                           phedema and metastasis, recent research spearheaded by the lau-
                                                                             reates and other researchers, has implicated the lymphatic
  Received: 11 October 2023.                                                 system in the pathogenesis of various diseases including obesity
  Accepted: 12 October 2023.                                                 and metabolic disease, inflammation, hypertension, cardiovas-
                                                                             cular disease such as atherosclerosis and myocardial infarction,
  Publisher’s note: all claims expressed in this article are solely those    as well as glaucoma and neurodegeneration (Figure 1E).1-3
  of the authors and do not necessarily represent those of their affili-
  ated organizations, or those of the publisher, the editors and the re-
                                                                                  Kari Alitalo’s work was instrumental in allowing research
  viewers. Any product that may be evaluated in this article or claim        on lymphatic vessels to progress into a full-blown discipline
  that may be made by its manufacturer is not guaranteed or endorsed         that is now pursued by many laboratories around the world. His
  by the publisher.                                                          laboratory discovered the VEGFR3 tyrosine kinase growth fac-
                                                                             tor receptor expressed on lymphatic vascular endothelial cells,
  ©
   Copyright: the Author(s), 2023                                            demonstrating for the first time that growth of lymphatic vessels
  Licensee PAGEPress, Italy
  Bleeding, Thrombosis and Vascular Biology 2023; 2:99
                                                                             is regulated differently from that of arteries or veins.4 He then
  doi:10.4081/btvb.2023.99                                                   discovered VEGF-C, which is the main ligand for VEGFR3 and
                                                                             the major lymphangiogenic growth factor known to date.5
  This work is licensed under a Creative Commons Attribution-                Kari’s lab characterized the molecular interaction between
  NonCommercial 4.0 International License (CC BY-NC 4.0).                    VEGF-C and VEGFR3 biochemically and structurally, and
                                                                             used genetic ablation in mice to show that removal of one allele


                                              Bleeding, Thrombosis and Vascular Biology 2023; 2:99
56                                                              A. Eichmann




Figure 1. Lymphatic vasculature function. A) Lymphatics return extravasated capillary fluid to the circulation (arrows) via lymph nodes.
B) They take up immune cells and control immunity and inflammation. C) Lymphatic dysfunction leads to lymphedema. D) Metastatic
tumor cells spread via the lymphatics. E) New lymphatic biology in health and disease.




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                                                                                           on
of Vegf-c, or removal of Vegfr3 is lethal due to ablation of lym-       ease. This observation holds true in patients and in mice,12 and
phatic vessel growth.6 This enabled foundational studies to un-         it provides strong rationale to give back the missing ANG1 pro-




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derstand the functions of the lymphatic vascular system in              tein in recombinant form as a treatment for these patients.
health and disease.
     In collaboration with geneticists and patient families, Kari’s
lab discovered human mutations in VEGFR-3 that cause inher-
                                                                              us
                                                                        Quaggin also showed that ANG1 additionally functions in the
                                                                        diabetic kidney vasculature to protect it from diabetic nephropa-
                                                                        thy, hence the ANG1 supplementation approach could be more
                                                                       al
ited lymphedema in patients.7 The growth-promoting ability of           widely relevant for diabetic nephropathy and microvascular di-
VEGF-C was tested in phase 1 clinical trials to prevent second-         abetic complications. Susan Quaggin’s work highlights the im-
                                                           ci

ary lymphedema in breast cancer patients that underwent sur-            portance of the lymphatic system in regulating ocular fluid
gical lymph node removal, with a successful reduction of arm            drainage in health and disease, and it exemplifies how basic sci-
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volume.8 Conversely, VEGF-C inhibitors can block experimen-             ence in lymphatic vascular biology can impact clinical practice.
tal lymph node metastasis in mice and are tested clinically for
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their ability to block neovessel growth in blinding eye diseases.9
These studies opened an active field of research that identified        References
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new biology associated with lymphatic vessels, which is much
more important than previously thought. Dr. Alitalo notably dis-         1. Donnan MD, Kenig-Kozlovsky Y, Quaggin SE. The lym-
covered many of these new lymphatic functions, including the                phatics in kidney health and disease. Nat Rev Nephrol
                                        -c




identification of a meningeal lymphatic drainage system that                2021;17:655-75.
contributes to brain waste drainage and that has become an in-           2. Brakenhielm E, Alitalo K. Cardiac lymphatics in health and
                                on




tense worldwide focus in neurological disease research.3                    disease. Nat Rev Cardiol 2019;16:56-68.
     Susan Quaggin is the Charles Horace Mayo Professor of               3. Oliver G, Kipnis J, Randolph GJ, Harvey NL. The lymphatic
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Medicine, Director of the Feinberg Cardiovascular Research                  vasculature in the 21st Century: novel functional roles in
Institute, and Chief of the Division of Nephrology at North-                homeostasis and disease. Cell 2020;182:270-96.
western University Feinberg School of Medicine. Work in her              4. Kaipainen A, Korhonen J, Mustonen T, et al. Expression of
laboratory addresses microvascular damage in diabetic patients,             the fms-like tyrosine kinase 4 gene becomes restricted to
which leads to kidney failure, blindness and nerve damage. She              lymphatic endothelium during development. Proc Natl Acad
revealed endothelial growth factor signaling mechanisms re-                 Sci USA 1995;92:3566-70.
quired for the formation and integrity of the vasculature in the         5. Joukov V, Pajusola K, Kaipainen A, et al. A novel vascular
eye and in the kidney. Notably, her laboratory made mouse                   endothelial growth factor, VEGF-C, is a ligand for the Flt4
models carrying cell-type specific and temporally inducible in-             (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases.
activation of the TIE2 receptor, and its Angiopoietin1 (ANG1)               EMBO J. 1996;15:290-8. Erratum in: EMBO J 1996;15:
ligand, to discover that these mutations specifically affect lym-           1751.
phatic drainage from the eye, leading to an increase in intro-           6. Karkkainen MJ, Haiko P, Sainio K, et al. Vascular endothe-
ocular pressure, open-angle glaucoma and blindness.10                       lial growth factor C is required for sprouting of the first lym-
     Next, with a team of clinicians and geneticists, they found            phatic vessels from embryonic veins. Nat Immunol
that human mutations in ANG1 and TIE2 are found in several                  2004;5:74-80.
families with primary congenital glaucoma.11 Quaggin showed              7. Karkkainen MJ, Ferrell RE, Lawrence EC, et al. Missense
that the mutations lead to a loss of function, with an autosomal            mutations interfere with VEGFR-3 signalling in primary
dominant inheritance pattern, meaning that reduced ligand-re-               lymphoedema. Nat Genet 2000;25:153-9.
ceptor signaling in patients is sufficient to induce glaucoma dis-       8. Leppäpuska IM, Hartiala P, Suominen S, et al. Phase 1 Lym-


                                         Bleeding, Thrombosis and Vascular Biology 2023; 2:99
                             The Lefoulon Delalande Foundation honors the lymphatic vascular system                              57



    factin® study: 24-month efficacy and safety results of com-         fect causes ocular hypertension and glaucoma in mice. J Clin
    bined adenoviral VEGF-C and lymph node transfer treat-              Invest 2014;124:4320-4.
    ment for upper extremity lymphedema. J Plast Reconstr           11. Souma T, Tompson SW, Thomson Bret al. Angiopoietin re-
    Aesthet Surg 2022;75:3938-45.                                       ceptor TEK mutations underlie primary congenital glaucoma
 9. Tammela T, Zarkada G, Wallgard E, et al. Blocking VEGFR-            with variable expressivity. J Clin Invest 2016;126:2575-87.
    3 suppresses angiogenic sprouting and vascular network for-     12. Thomson BR, Souma T, Tompson SW, et al. Angiopoietin-
    mation. Nature 2008;454:656-60.                                     1 is required for Schlemm's canal development in mice and
10. Thomson BR, Heinen S, Jeansson M, et al. A lymphatic de-            humans. J Clin Invest 2017;127:4421-36.




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