Cooper-McLure Professor of Medicine
Director, Center for Vascular Biology
Penn Cardiovascular Institute, Perelman School of Medicine
Location: Smilow TRC 11-123
Admin: Christine Maschak
Our lab investigates signaling pathways that regulate cardiovascular biology and diseases. We are interested in both lymphatic and blood vessel regulatory pathways, and in the interactions between blood cells and vascular endothelium. Most of the pathways we investigate are known to cause human vascular diseases. We apply vertebrate genetic approaches as well as biochemical and state of the art molecular approaches to understand the function of these pathways during normal development and in disease models.
Cerebral Cavernous Malformation (CCM):
CCMs cause stroke and seizure in young people, many of whom carry a mutant disease allele. The CCM pathway is required in endothelial cells to prevent the formation of vascular malformations in the brain and central nervous system. Our studies have used mouse, human and zebrafish genetics, ex vivo endothelial cell systems and biochemical approaches to define how the CCM proteins function to inhibit the MEKK3-KLF2/4 signaling pathway in endothelial cells. Ongoing projects address the upstream activators of this pathway, the downstream effectors by which cavernous malformations are formed, and the translation of discoveries in mice to human CCM patients.
Heart and blood vessel development:
We are investigating the role of several signaling pathways, including the CCM pathway and MEKK3-KLF2/4 signaling, in the development of the heart and blood vessels. These studies have demonstrated a critical role of KLF2/4 signaling in the formation of heart valves in response to hemodynamic forces as well as in other areas of blood and vascular development. Ongoing studies are examining the role of this pathway in the heart and peripheral vasculature during embryonic development in the mouse.
Lymphatic vascular signaling:
We have a long-standing interest in how lymphatic vessels form during development, the organ-specific roles that lymphatic vessels play in health and disease, and lympho-venous hemostasis.
Lymphatic vascular development:
Areas of active investigation related to lymphatic development include the roles of CCBE1, ADAMTS3 and VEGFC in directing lymphatic vascular growth, role of lymph flow in lymphatic vessel maturation and the formation of lymphatic valves, and the mechanisms by which blood and lymphatic vessels are maintained as separate networks despite being directly connected. Ongoing projects are utilizing genetic models and ex vivo cellular systems to understand how proteolytic activation of the VEGFC and VEGFD ligands controls lymphatic growth.
Over a period of >10 years we have identified a mechanism of platelet activation in which lymphatic endothelial Podoplanin activates platelet CLEC2 receptors to drive an inter-vascular form of hemostasis known as lympho-venous hemostasis. This mechanism is required to prevent blood from filling the lower pressure lymphatic network and to maintain normal lymphatic function. Ongoing studies are addressing how this system balances the forward flow of lymph with the need to block the backward flow of blood and with the role of this mechanism in pathologic states in animal models and human diseases.
Role of flow in lymphatic valve formation:
Analysis of CLEC2-deficient animals revealed evidence that lymph flow is required for normal lymphatic valve formation and maturation of the lymphatic collecting system. Ongoing studies are examining lymphatic endothelial molecular pathways activated by lymph flow and how they control valve formation.
Fluid shear forces:
We have a long-standing interest in how fluid forces regulate the development of the heart, blood vessels and lymphatic vessels and its function after development. We focus on endothelial signaling pathways activated by fluid shear forces and their role in the developing and mature vasculature and heart.
KLF2 regulation of heart valve formation:
We have studied the role of KLF2 in mediating hemodynamic-dependent responses during heart and blood vessel development. Most recently, we have identified a KLF2 signaling pathway that is directs the formation of heart valves by orchestrating the remodeling of cardiac cushions to valve leaflets
Integration of hemodynamic signals in cardiovascular development:
We have several projects that examine how hemodynamic signals are converted to genetic instructions in endothelial cells in the developing embryo and the mature animal (e.g. KLF2 or GATA2-FOXC2 transcriptional events).
The role of the endothelium in hemostasis and thrombosis:
Our lab has studied numerous platelet signaling pathways, including GPVI, CLEC2, and platelet integrins. Our recent work is focused on the role of the vascular endothelium in both activating and prevent hemostasis.
CLEC2-mediated platelet activation:
Our studies identify platelet CLEC2 receptors as a key mechanism by which hemostasis is triggered in response to the transmembrane ligand Podoplanin. The primary role of this pathway is for lympho-venous hemostasis, an area of focus for our lab.
Endothelial spatial regulation of hemostasis:
We are studying endothelial heterogeneity as it relates to control of hemostasis and thrombosis in vivo.
- Reed HO, Wang L, Sonett J, Chen M, Yang J, Li L, Aradi P, Jakus Z, D'Armiento J, Hancock WW, Kahn ML. Lymphatic impairment leads to pulmonary tertiary lymphoid organ formation and alveolar damage. J Clin Invest. 2019 Apr 4;130:2514-2526. doi: 10.1172/JCI125044.
- Sweet DT, Hall JD, Welsh J, Kahn ML, Jiménez JM. Investigating Effects of Fluid Shear Stress on Lymphatic Endothelial Cells. Methods Mol Biol. 2018;1846:213-227. doi: 10.1007/978-1-4939-8712-2_14. PMID: 30242762
- Goddard LM, Duchemin AL, Ramalingan H, Wu B, Chen M, Bamezai S, Yang J, Li L, Morley MP, Wang T, Scherrer-Crosbie M, Frank DB, Engleka KA, Jameson SC, Morrisey EE, Carroll TJ, Zhou B, Vermot J, Kahn ML. Hemodynamic Forces Sculpt Developing Heart Valves through a KLF2-WNT9B Paracrine Signaling Axis. Dev Cell. 2017 Nov 6;43(3):274-289.e5. doi: 10.1016/j.devcel.2017.09.023. Epub 2017 Oct 19. PMID: 29056552
- Goddard LM, Kahn ML. A BMPy Road for Venous Development. Dev Cell. 2017 Sep 11;42(5):435-436. doi: 10.1016/j.devcel.2017.08.016. PMID: 28898672
- Tang AT, Choi JP, Kotzin JJ, Yang Y, Hong CC, Hobson N, Girard R, Zeineddine HA, Lightle R, Moore T, Cao Y, Shenkar R, Chen M, Mericko P, Yang J, Li L, Tanes C, Kobuley D, Võsa U, Whitehead KJ, Li DY, Franke L, Hart B, Schwaninger M, Henao-Mejia J, Morrison L, Kim H, Awad IA, Zheng X, Kahn ML. Endothelial TLR4 and the microbiome drive cerebral cavernous malformations. Nature. 2017 May 18;545(7654):305-310. doi: 10.1038/nature22075. Epub 2017 May 10. PMID: 28489816
- Welsh JD, Kahn ML, Sweet DT. Lymphovenous hemostasis and the role of platelets in regulating lymphatic flow and lymphatic vessel maturation. Blood. 2016 Sep 1;128(9):1169-73. doi: 10.1182/blood-2016-04-636415. Epub 2016 Jul 6. Review. PMID: 27385789
- Zhou Z, Tang AT, Wong WY, Bamezai S, Goddard LM, Shenkar R, Zhou S, Yang J, Wright AC, Foley M, Arthur JS, Whitehead KJ, Awad IA, Li DY, Zheng X, Kahn ML. Corrigendum: Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4 signalling. Nature. 2016 Aug 25;536(7617):488. doi: 10.1038/nature18311. Epub 2016 May 25. No abstract available. PMID: 27281211