About

Mark L. Kahn, M.D., is the Edward S. Cooper, M.D./Norman Roosevelt and Elizabeth Meriwether McLure Professor at the Perelman School of Medicine at the University of Pennsylvania. He is a faculty member in the Department of Medicine, with clinical expertise in general cardiology, and holds positions on the medical staff at the Department of Veteran's Affairs Medical Center and the Hospital of the University of Pennsylvania. Dr. Kahn's research focuses on signaling pathways in cardiovascular development and function, particularly in the areas of angiogenesis and platelet signaling. His laboratory investigates mechanisms regulating vascular development, including the role of Syk and SLP-76 signaling in lymphatic vascular development, and the function of platelet immune receptors such as GPVI and CLEC2 in hemostasis and vascular interactions. Additionally, his work explores the role of the cerebral cavernous malformation (CCM) signaling pathway in vascular development and disease, aiming to understand how this pathway influences endothelial function and vascular malformations. Dr. Kahn's contributions include elucidating how platelets control endothelial function and lymphatic vascular development, as well as investigating genetic mutations associated with vascular diseases. His research employs mouse and fish models to study these pathways, with the goal of advancing understanding of vascular biology and developing potential therapeutic strategies.

Research topics

• Biology
• Neuroscience
• Medicine
• Pathology
• Bioinformatics
• Genetics
• Cancer research
• Cell biology
• Internal medicine

Selected publications

• TIE2 links MEKK3–KLF2/4 and PI3K signaling in cerebral cavernous malformation

  The Journal of Experimental Medicine · 2026-03-27

  articleSenior author

  Cerebral cavernous malformations (CCMs) are vascular lesions in the central nervous system that can cause strokes and seizures. Aggressive CCM growth follows an endothelial cell two-hit mechanism in which enhanced MEKK3-KLF2/4 signaling stimulates PI3K signaling, but how these pathways are linked has been undefined. Here, we use human CCM specimens, two mouse models of CCM disease, and primary human endothelial cells to examine the roles of the major endothelial growth factor receptors, VEGFR2 and TIE2. We find no evidence of augmented VEGFR2 signaling in CCM lesions, and neither genetic nor pharmacologic blockade of VEGFR2 reduced CCM formation in mouse models. Instead, we observe markedly increased phospho-TIE2 levels in human and mouse CCM lesions, MEKK3-KLF2/4-driven induction of TIE2 receptor expression, and almost complete rescue of CCM formation following genetic or pharmacologic TIE2 blockade in mouse models. Our studies identify TIE2 as the molecular link between the MEKK3-KLF2/4 and PI3K signaling pathways during CCM formation and suggest that targeting TIE2 may be an effective means to treat human CCM disease.

  PublisherDOI

• Dll4 assembles the umbilical cord and placental vasculature

  JCI Insight · 2026-02-17 · 1 citations

  articleOpen accessSenior author

  Proper development of the umbilical cord and placental vasculature is essential for embryonic development. While the allantois is known give rise to endothelial cells (ECs) within the placenta, whether the allantois gives rise to ECs in the umbilical cord is debated. Furthermore, a lack of genetic tools to study placental vascular development independent of the embryo proper has hindered robust investigation into the primary cause of vascular defects from early studies utilizing global KOs. In this study, we delineate the contribution of the allantois to the umbilical vessels and utilize a mouse genetic tool previously developed by our lab to revisit the role of Notch signaling during placental development. We show that the allantois has mosaic contribution to the umbilical endothelium with higher contributions closer to the placenta. Allantoic deletion of Dll4 disrupts umbilical cord and placental vascular formation with secondary defects in the heart. Lastly, we identify Unc5b downstream of Notch signaling that restricts EC migration while promoting chemokine signaling for vascular smooth muscle cell (vSMC) recruitment to arteries. These findings identify a genetic tool for investigating placental vascular development and give insights into the ontogeny and mechanisms of placental vascular and umbilical cord development.

  PublisherDOI

• HTRS2025.P1.48 Human Lymphatic Fluid Supports Coagulation Driven Primarily by the Extrinsic Pathway

  Research and Practice in Thrombosis and Haemostasis · 2025-11-01

  articleOpen access
  PublisherDOI

• Hemodynamic forces prevent myxomatous valve disease in mice through KLF2/4 signaling

  Journal of Clinical Investigation · 2025-06-15 · 2 citations

  articleOpen accessSenior authorCorresponding

  Myxomatous valve disease (MVD) is the most common form of cardiac valve disease in the developed world. A small fraction of MVD is syndromic and arises in association with matrix protein defects such as those in Marfan syndrome, but most MVD is acquired later in life through an undefined pathogenesis. The KLF2/4 transcription factors mediate endothelial fluid shear responses, including those required to create cardiac valves during embryonic development. Here we test the role of hemodynamic shear forces and downstream endothelial KLF2/4 in mature cardiac valves. We find that loss of hemodynamic forces in heterotopically transplanted hearts or genetic deletion of KLF2/4 in cardiac valve endothelium confers valve cell proliferation and matrix deposition associated with valve thickening, findings also observed in mice expressing the mutant fibrillin-1 protein known to cause human MVD. Transcriptomic and histologic analysis reveals increased monocyte recruitment and TGF-β signaling in both fibrillin-1-mutant valves and valves lacking hemodynamic forces or endothelial KLF2/4 function, but only loss of TGF-β/SMAD signaling rescued myxomatous changes. We observed reduced KLF2/4 expression and augmented SMAD signaling in human MVD. These studies identify hemodynamic activation of endothelial KLF2/4 as an environmental homeostatic regulator of cardiac valves and suggest that non-syndromic MVD may arise in association with disturbed blood flow across the aging valve.

  PublisherDOI

• Lineage tracing studies suggest that the placenta is not a de novo source of hematopoietic stem cells

  PLoS Biology · 2025-01-28 · 3 citations

  articleOpen accessSenior authorCorresponding

  Definitive hematopoietic stem and progenitor cells (HSPCs) arise from a small number of hemogenic endothelial cells (HECs) within the developing embryo. Understanding the origin and ontogeny of HSPCs is of considerable interest and potential therapeutic value. It has been proposed that the murine placenta contains HECs that differentiate into HSPCs. However, during human gestation HSPCs arise in the aorta considerably earlier than when they can first be detected in the placenta, suggesting that the placenta may primarily serve as a niche. We found that the Runx1 transcription factor, which is required to generate HSPCs from HECs, is not expressed by mouse placental ECs. To definitively determine whether the mouse placenta is a site of HSPC emergence, we performed lineage tracing experiments with a Hoxa13Cre allele that specifically labels ECs in the placenta and umbilical cord (UC), but not in the yolk sac or embryo. Immunostaining revealed Hoxa13Cre lineage-traced HECs and HSPCs in the UC, a known site of HECs, but not the placenta. Consistent with these findings, ECs harvested from the E10.5 aorta and UC, but not the placenta, gave rise to hematopoietic cells ex vivo, while colony forming assays using E14.5 fetal liver revealed only 2% of HSPCs arose from Hoxa13-expressing precursors. In contrast, the pan-EC Cdh5-CreERT2 allele labeled most HSPCs in the mouse placenta. Lastly, we found that RUNX1 and other HEC genes were not expressed in first-trimester human placenta villous ECs, suggesting that human placenta is not hemogenic. Our findings demonstrate that the placenta functions as a site for expansion of HSPCs that arise within the embryo proper and is not a primary site of HSPC emergence.

  PublisherDOI

• Artery formation in the intestinal wall and mesentery by intestine-derived Esm1+ endothelial cells

  Nature Communications · 2025-09-25 · 5 citations

  articleOpen access

  Abstract Arterial blood transport into peripheral organs is indispensable for developmental growth, homeostasis and tissue repair. While it is appreciated that defective formation or compromised function of arteries is associated with a range of human diseases, the cellular and molecular mechanisms mediating arterial development remain little understood for most organs. Here, we show with genetic approaches that a small subpopulation of endothelial cells inside the intestinal villi of the embryonic mouse, characterized by the expression of endothelial cell-specific molecule 1 (Esm1/endocan), gives rise to arterial endothelium in the intestinal wall but also in the distant mesenteric vasculature. This involves cell migration but also substantial changes in morphology and gene expression. Immunohistochemistry and single cell RNA-sequencing confirm that intestinal Esm1 + cells have a distinct molecular profile and the capacity to undergo arterial differentiation. Genetic approaches establish that artery formation by the progeny of Esm1 + cells requires integrin β1 and signaling by the growth factor VEGF-C and its receptor VEGFR3. The sum of these findings demonstrates that Esm1 + cells inside the villus capillary network contribute to the formation of intestinal and mesenteric arteries during development.

  PublisherOA PDFDOI

• Human Lymphatic Fluid Supports Coagulation Driven Primarily By the Extrinsic Pathway

  Blood · 2024-11-05 · 1 citations

  articleOpen access

  The lymphatic system is a network of vessels, tissues, and organs whose main function is to maintain fluid balance. Lymphatic vessels form a unidirectional conduit system that traffics fluid derived from cell exudate and blood capillary leakage back to the bloodstream via the subclavian veins. This exchange introduces the potential for proteins from the blood to infiltrate the lymphatic system. Accordingly, previous analyses of lymphatic fluid, albeit limited, have established the presence of coagulation factors. Depending on their composition and concentration, these coagulation factors could present a risk for thrombosis in lymphatic fluid, especially when concurrent with other pathological conditions. For instance, although reports of thrombosis within the lymphatic system are rare, disruptions of blood flow, like those in cardiac conditions, can cause lymphedema and contribute to a hypercoagulable state. However, the current body of research lacks a comprehensive evaluation of coagulation within lymphatic fluid, thereby leaving our understanding of lymphatic thrombosis largely undefined. Here we evaluated coagulation in thoracic duct lymphatic fluid collected from pediatric patients at the Children's Hospital of Philadelphia. Coagulation of lymphatic fluid samples was evaluated using a thrombin generation assays (TGAs) as well as prothrombin time (PT) and activated partial thromboplastin time (aPTT) clotting assays. We also characterized antigen concentrations of major clotting factors using ELISAs. In TGAs initiated with low tissue factor (TF; 0.1 pM), most lymphatic fluid from patient samples (n= 52) had thrombin generation (TG) profiles comparable to pooled normal plasma (PNP). Average peak thrombin (IIa) and endogenous thrombin potential (ETP) were around 75% of PNP at 166.2 +/- 17.27 nM and 3185.7 +/- 314.3 nM*min, respectively. Lag times of lymphatic samples were slightly prolonged with an average of 14.1 +/- 1.9 min compared to PNP (10.2 +/- 1.4 min). Consistent with these results, lymphatic fluid samples also demonstrated appreciable clotting activity in PT assays, with most samples having a twofold increase in clot time in comparison to PNP (31.7 +/- 4.3 sec lymph vs. 13.6 +/- 0.6 sec PNP). In contrast to TF-initiated TGAs, initiation via the intrinsic pathway using a dilute aPTT reagent generally produced a weak TG profile (peak IIa: 86.9 +/- 15.4 nM, ETP: 2474.2 +/- 303.8 nM*min, lag time: 22.4 +/- 2.2 min) compared to PNP (peak IIa: 281.2 +/- 20.2 nM, ETP: 4195.58 +/- 279.1 nM*min, lag time: 21.25 +/- 3.75). These lymphatic fluid samples also had markedly prolonged aPTT clotting times compared to both PNP (32.6 +/- 0.4 sec) and FVIII deficient plasmas (96.1 +/- 3.0 sec). These findings suggest concentrations of one or more clotting factors involved in the intrinsic pathway may be low in lymphatic fluid compared to normal plasma. Coagulation assays of lymphatic fluid were supported by measurement of several key coagulation factors. ELISA data for FVIII revealed levels at 30% of PNP concentrations, which is consistent with antigen levels observed in moderate hemophilia A plasma (a FVIII deficiency with 5-40% of PNP antigen levels). Fibrinogen levels were also notably low at 30% of plasma concentrations. In contrast, FV antigen concentrations were just below the normal range of 50-150% antigen level at 43% while lymphatic FIX and FX antigen were above 50%, suggesting that none of these factors is limiting for coagulation in lymphatic fluid. Because lymphatic endothelial cells are known to express thrombomodulin, we also tested lymphatic samples for evidence of a functional Protein C (PC) pathway. The addition of soluble thrombomodulin to lymphatic fluid in TF-initiated TGAs produced a robust anti-thrombogenic effect comparable to a PNP control, confirming the presence of functional PC anticoagulant activity in lymphatic fluid. These data support further investigation of other anticoagulant regulators (e.g. antithrombin, tissue factor pathway inhibitor) in lymphatic fluid. Together these data confirm that human lymphatic fluid supports thrombin generation and clot formation in vitro, and this procoagulant activity is primarily TF-dependent. Further analysis of additional components of the pro- and anticoagulant pathways will provide a more complete understanding of coagulation in the lymphatic system and its potential to contribute to lymphatic thrombosis.

  PublisherOA PDFDOI

• GPR124 regulates murine brain embryonic angiogenesis and BBB formation by an intracellular domain-independent mechanism

  Development · 2024-04-29 · 11 citations

  articleOpen access

  The GPR124/RECK/WNT7 pathway is an essential regulator of CNS angiogenesis and blood-brain barrier (BBB) function. GPR124, a brain endothelial adhesion seven-pass transmembrane protein, associates with RECK, which binds and stabilizes newly synthesized WNT7 that is transferred to frizzled (FZD) to initiate canonical β-catenin signaling. GPR124 remains enigmatic: although its extracellular domain (ECD) is essential, the poorly conserved intracellular domain (ICD) appears to be variably required in mammals versus zebrafish, potentially via adaptor protein bridging of GPR124 and FZD ICDs. GPR124 ICD deletion impairs zebrafish angiogenesis, but paradoxically retains WNT7 signaling upon mammalian transfection. We thus investigated GPR124 ICD function using the mouse deletion mutant Gpr124ΔC. Despite inefficiently expressed GPR124ΔC protein, Gpr124ΔC/ΔC mice could be born with normal cerebral cortex angiogenesis, in comparison with Gpr124-/- embryonic lethality, forebrain avascularity and hemorrhage. Gpr124ΔC/ΔC vascular phenotypes were restricted to sporadic ganglionic eminence angiogenic defects, attributable to impaired GPR124ΔC protein expression. Furthermore, Gpr124ΔC and the recombinant GPR124 ECD rescued WNT7 signaling in culture upon brain endothelial Gpr124 knockdown. Thus, in mice, GPR124-regulated CNS forebrain angiogenesis and BBB function are exerted by ICD-independent functionality, extending the signaling mechanisms used by adhesion seven-pass transmembrane receptors.

  PublisherOA PDFDOI

• YAP/TAZ signaling in allantois-derived cells is required for placental vascularization

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-09-16 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Normal placental development and angiogenesis are crucial for fetal growth and maternal health during pregnancy. However, molecular regulation of placental angiogenesis has been difficult to study due to a lack of specific genetic tools that isolate the placenta from the embryo and yolk sac. To address this gap in knowledge we recently developed Hoxa13 Cre mice in which Cre is expressed in allantois-derived cells, including placental endothelial and stromal cells. Mice lacking the transcriptional regulators Yes-associated protein (YAP) and PDZ-binding motif (TAZ) in allantois-derived cells exhibit embryonic lethality at midgestation with compromised placental vasculature. snRNA-seq analysis revealed transcriptional changes in placental stromal cells and endothelial cells. YAP/TAZ mutants exhibited significantly reduced placental stromal cells prior to the endothelial architectural change, highlighting the role of these cells in placental vascular growth. These results reveal a central role for YAP/TAZ signaling during placental vascular growth and implicate Hoxa13 -derived placental stromal cells as a critical component of placental vascularization.

  PublisherOA PDFDOI

• CCM Function in the Heart

  JACC Basic to Translational Science · 2024-02-01

  editorialOpen access1st authorCorresponding

  [Figure: see text]

  PublisherDOI

Recent grants

• NIH Grant R01HL072798

  NIH · $3.5M · 2013

• NIH Grant R01HL081654

  NIH · $1.9M · 2012

• Signaling Aberrations and Cerebral Cavernous Malformation Pathogenesis

  NIH · $25.9M · 2015–2025

• NIH Grant R01HL103432

  NIH · $1.6M · 2015

• NIH Grant R01HL102138

  NIH · $2.6M · 2015

Frequent coauthors

• Jisheng Yang

  74 shared

• Alan T. Tang

  University of Pennsylvania

  68 shared

• Xiangjian Zheng

  49 shared

• François Lanza

  Université de Strasbourg

  41 shared

• Robert Shenkar

  University of Chicago

  40 shared

• Douglas A. Marchuk

  Duke University

  39 shared

• Benjamin Kleaveland

  Weill Cornell Medicine

  39 shared

• Issam A. Awad

  University of Chicago

  38 shared

Labs

• Kahn Lab (CVI)PI