Description of Research Expertise

Research Interests
Signaling pathways in angiogenesis and hemostasis.

Key words: Angiogenesis, vascular development, platelet, signaling.

Description of Research
My laboratory investigates signaling pathways in cardiovascular development and function. We have two general areas of interest: angiogenesis and platelet signaling. In some cases these areas intersect, e.g. the role of Syk and SLP-76 signaling downstream of platelet receptors that regulate lymphatic vascular development. Major projects in the lab include the following: Regulation of lymphatic vascular development by Syk and SLP-76 signaling. Mice lacking Syk or SLP-76 exhibit lethal vascular phenotypes that we have recently found to be due to a failure to separate emerging lymphatic vessels from pre-existing blood vessels. We have recently identified platelet interaction with lymphatic endothelial cells as the basis for this mechanism of vascular regulation. The long term goals of this project are to understand how platelets control endothelial function and lymphatic vascular development. Platelet immunoreceptor signaling. There are two platelet-specific immune-type receptors, GPVI and CLEC2, that activate Syk and SLP-76 signals. GPVI is a collagen receptor that functions in hemostasis and thrombosis. CLEC2 is a receptor for the lymphatic endothelial protein PDPN and regulates blood-lymphatic vascular interactions. We are presently using mouse genetic models to understand how these two receptors signal and to define their biological roles in vivo. Role of cerebral cavernous malformation (CCM) signaling pathway in vascular development and disease. CCMs are a common human vascular disease caused by loss of function mutations in 3 CCM proteins. We have recently shown that the Heart of Glass (HEG) receptor and CCM proteins are required in mouse and fish cardiovascular development. We are actively investigating how this recently identified pathway regulates endothelial function in development and causes CCMs.

Rotation Projects
1. Regulation of lymphatic vascular development by platelet signaling. 2. HEG-CCM signaling in fish and mouse models. 3. Novel receptor signaling pathways in mammalian cardiovascular development. 4. Development and application of lymphatic endothelial-specific gene knockouts.

Lab personnel:
Xiangjain Zheng, PhD-postdoctoral fellow; Zhiyng Zou, PhD-postdoctoral fellow; Cara Bertozzi, PhD student; Chiu-Yu Chen, MD-PhD student; Alec Schmaier, PhD student; Chong Xu, PhD-postdoctoral fellow; Jiping Xiao, PhD-postdoctoral fellow; Patricia Mericko, Lab Manager; Mei Chen Research, Specialist.

Selected Publications

Tang AT, Buchholz DW, Szigety KM, Imbiakha B, Gao S, Frankfurter M, Wang M, Yang J, Hewins P, Mericko-Ishizuka P, Leu NA, Sterling S, Monreal IA, Sahler J, August A, Zhu X, Jurado KA, Xu M, Morrisey EE, Millar SE, Aguilar HC, Kahn ML: Cell-autonomous requirement for ACE2 across organs in lethal mouse SARS-CoV-2 infection. PLoS Biol. : 2023.

Chen X, Tang AT, Tober J, Yang J, Leu NA, Sterling S, Chen M, Yang Y, Mericko-Ishizuka P, Speck NA, Kahn ML: Mouse placenta fetal macrophages arise from endothelial cells outside the placenta Developmental Cell : 2022.

Sung D, Chen M, Dominguez M, Mahadevan A, Chen X, Yang J, Gao S, Ren A, Tang A, Mericko P, Patton R, Lee M, Janaway M, Nottebaum A, Vestweber D, Scallan J, Kahn M: Sinusoidal and lymphatic vessel growth is controlled by reciprocal VEGF-C–CDH5 inhibition Nature Cardiovascular Research : 2022.

Muratoglu SC, Charette MF, Galis ZS, Greenstein AS, Daugherty A, Joutel A, Kozel BA, Wilcock DM, Collins EC, Sorond FA, Howell GR, Hyacinth HI, Lloyd KKC, Stenmark KR, Boehm M, Kahn ML, Corriveau R, Wells S, Bussey TJ, Sukoff Rizzo SJ, Iruela-Arispe ML: Perspectives on Cognitive Phenotypes and Models of Vascular Disease Arterioscler Thromb Vasc Biol : 2022.

Yang Y, Mumau M, Tober J, Zhu Q, Bennett L, Hong C, Sung D, Keller T, Uzun Y, Gao P, Shewale S, Chen M, Yang J, Chen X, Thomas SA, Tan K, Speck NA, Kahn ML.: Endothelial MEKK3-KLF2/4 signaling integrates inflammatory and hemodynamic signals during definitive hematopoiesis Blood : 2022.

Sung DC, Chen X, Chen M, Yang J, Schultz S, Babu A, Xu Y, Gao S, Keller TCS 4th, Mericko-Ishizuka P, Lee M, Yang Y, Scallan JP, Kahn ML.: VE-cadherin enables trophoblast endovascular invasion and spiral artery remodeling during placental development, Elife 11 (e77241): 2022.

Keller IV TCS, Lim L, Shewale S, McDaid K, Marti-Pamies I, Tang AT, Wittig C, Guerrero AA, Sterling S, Leu NA, Scherrer-Crosbie M, Gimotty PA, and Kahn, ML: Genetic Blockade of Lymphangiogenesis does not Impair Cardiac Function after Myocardial Infarction Journal of Clinical Investigation : 2021.

Ren AA, Snellings DA, Su SY, Hong CC, Castro M, Tang AT, Detter MR, Hobson N, Girard R, Romanos S, Lightle R, Moore T, Shenkar R, Benavides C, Beaman MM, Helge Mueller-Fielitz H, Chen M, Mericko P, Yang J, Sung DC, Lawton MT, Ruppert M, Schwaninger M, Körbelin J, Potente M, Awad IA, Marchuk DA and Kahn ML: PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism Nature 594 (7862): 271-276,2021.

Snellings DA, Hong CC, Ren AA, Lopez-Ramirez MA, Girard R, Srinath A, Marchuk DA, Ginsberg MH, Awad IA, Kahn ML: Cerebral Cavernous Malformation: From Mechanism to Therapy Circulation Research 129 (1): 195-215,2021.

Stratman AN, Burns MC, Farrelly OM, Davis AE, Li W, Pham VN, Castranova D, Yano JJ, Goddard LM, Nguyen O, Galanternik MV, Bolan TJ, Kahn ML, Mukouyama YS, Weinstein BM: Chemokine mediated signalling within arteries promotes vascular smooth muscle cell recruitment Communications Biology : 2020.

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Academic Contact Information

11-123 Smilow Center for Translational Research
3400 Civic Center Boulevard, Bldg. 421
Philadelphia, PA 19104-5159
Phone: 215-898-9007