Lymphatic vessels are a crucial but often overlooked component of the cardiovascular system. These specialised vessels return interstitial fluid and protein to the bloodstream, absorb lipids from the digestive tract, and traffic cells of the immune system. Abnormalities in the growth, development and function of lymphatic vessels are associated with human disorders including vascular malformations, lymphoedema, inflammatory diseases and cancer. Despite the integral role that lymphatic vessels play in health and disease, little is known about the signals that direct their construction.
Our research seeks to understand how the growth and development of lymphatic vessels (lymphangiogenesis) is controlled during embryonic development and in disease states. We utilise the mouse as a model system in which to study lymphangiogenesis in vivo, and in addition employ a wide range of molecular and cell biological techniques to dissect key lymphangiogenic signalling pathways in vitro. Our ultimate aim is that by understanding how lymphatic vessels are built, we will identify new opportunities to modulate this process and thereby provide more effective treatments for patients suffering from lymphatic vascular diseases.
Current research projects
- Elucidating the genetic basis of human lymphatic vessel disorders
- Understanding how lymphatic endothelial cell identity is transcriptionally programmed
- Characterising gene function in lymphatic vascular development
- Understanding how valves are built
- High resolution imaging of lymphatic vessel growth and development
Betterman KL and Harvey NL. The lymphatic vasculature: development and role in shaping immunity. Immunol Rev. 271(1):276-92, 2016.
Kazenwadel J and Harvey NL. Morphogenesis of the lymphatic vasculature: A focus on new progenitors and cellular mechanisms important for constructing lymphatic vessels. Dev Dyn. 245(3):209-19, 2016
Kazenwadel J, Betterman KL, Chong CE, Stokes PH, Lee YK, Secker GA, Agalarov Y, Demir CS, Lawrence DM, Sutton DL, Tabruyn SP, Miura N, Salminen M, Petrova TV, Matthews JM, Hahn CN, Scott HS and Harvey NL. GATA2 is required for lymphatic vessel valve development and maintenance. J Clin Invest. 125(8):2979-94, 2015.
Secker GA and Harvey NL. VEGFR signaling during lymphatic vascular development; from progenitor cells to functional vessels. Dev Dyn. 244(3):323-31, 2015.
Koltowska, K., K. L. Betterman, N. L. Harvey and B. M. Hogan."Getting out and about: the emergence and morphogenesis of the vertebrate lymphatic vasculature."Development 140: 1857-1870. (2013)
Kazenwadel J*, Secker GA*, Liu YJ*, Rosenfeld JA, Wildin RS, Cuellar-RodriguezJ, Hsu AP, Dyack S, Fernandez CV, Chong C, Babic M, Bardy PG, Shimamura A, ZhangM, WalshT, HollandSM, HicksteinDD, HorwitzMS, HahnCN, ScottHS* and HarveyNL*. “Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature.” Blood 119(5):1283-91.(2012) * Equal contribution
Betterman, K. L., S. Paquet-Fifield, M. L. Asselin-Labat, J. E. Visvader, L. M. Butler, S. A. Stacker, M. G. Achen and N. L. Harvey. "Remodeling of the lymphatic vasculature during mouse mammary gland morphogenesis is mediated via epithelial-derived lymphangiogenic stimuli." Am J Pathol 181: 2225-2238. (2012)
Kazenwadel, J., G. A. Secker, K. L. Betterman and N. L. Harvey. "In vitro assays using primary embryonic mouse lymphatic endothelial cells uncover key roles for FGFR1 signalling in lymphangiogenesis." PLoS One 7: e40497. (2012)
Gordon EJ, Rao S, Pollard JW, Nutt SL, Lang RA and Harvey NL. “Macrophages define dermal lymphatic vessel caliber during development by regulating lymphatic endothelial cell proliferation.” Development 137: 3899-910. (2010)
Kazenwadel J, Michael MZ and Harvey NL. Prox1 expression is negatively regulated by miR-181 in endothelial cells. Blood 116: 2395-401. (2010).