Cardiovascular Research at Penn

Mark L. Kahn, MD, BA
Office Phone: 215-898-5001 Lab Phone: 215-573-7069 Fax: 215-573-7884


The Kahn Lab investigates the signaling pathways that regulate vascular biology and disease, with an interest in both lymphatic and blood vessel regulatory pathways, and in the interactions between blood cells and vascular endothelium. Many of the pathways investigated are known to cause human vascular diseases. The Kahn Lab applies vertebrate genetic approaches to understanding the function of those pathways during normal development and in disease models, primarily through the use of mouse genetic models for in vivo studies. Zebrafish studies and avian models are also incorporated to complement the mouse models.

Research Projects

Our lab investigates signaling pathways that regulate vascular biology and disease.

The major areas of research in the Kahn Lab include:

We are interested in both lymphatic and blood vessel regulatory pathways, and in the interactions between blood cells and vascular endothelium. Many of the pathways we investigate are known to cause human vascular diseases and we apply vertebrate genetic approaches to understanding the function of those pathways during normal development and in disease models. We primarily use mouse genetic models for in vivo studies and also incorporate zebrafish studies and avian models to complement the mouse.

Lymphatic Vascular Biology

The lab is deeply invested in understanding the signaling pathways and functional roles of the lymphatic vascular network. In contrast to blood vessel development and growth, relatively little is understood regarding the mechanisms that control lymphatic vessel growth. Active projects in this area in the lab are described below.

  • Regulation of blood-lymphatic vascular separation by PODOPLANIN-CLEC2 signaling

    Our laboratory discovered that mice lacking the hematopoietic signaling proteins SYK and SLP-76 exhibit blood-filled lymphatics from the inception of lymphatic growth and died postnatally due to bloody and chylous ascites.

    Bone marrow transplantation studies revealed an essential role for blood cells in this mechanism, and embryo chimera experiments first suggested a cell autonomous mechanism, consistent with a role for hematopoietic endothelial progenitors in lymphatic development {Rafii, 2003 #1271; Sebzda, 2006 #940}. However, rigorous genetic lineage tracing studies failed to demonstrate any contribution of blood-derived cells to lymphatic endothelium, and the cellular mechanism of this pathway remained obscure until it was discovered that mice lacking PODOPLANIN, a cell surface protein found on lymphatic but not blood endothelial cells, exhibited an identical vascular phenotype.

    Subsequent studies have demonstrated that PODOPLANIN binds and activates CLEC2, a novel platelet receptor coupled to SYK and SLP-76, and that CLEC2 was also required in this pathway. These studies have identified a novel pathway by which platelets separate blood and lymphatic vessels during lymphatic vascular growth and in mature animals. Ongoing experiments are addressing the role of platelet activation in regulating lymphatic vascular growth.

  • Control of lymphangiogenesis by CCBE1

    Despite the vast differences between blood and lymphatic vessel function and growth, molecular and genetic studies have identified only one signaling pathway, VEGFC-VEGFR3, that specifically regulates lymphatic vessel growth. In addition, all the lymphangiogenic factors identified to date are either close cousins of known blood angiogenic factors (e.g. VEGFC) or have shared roles in both systems. A new and major focus of our lab is a recently described factor, CCBE1, that is required for the development and growth of lymphatic but not blood vessels.

    CCBE1 is a highly conserved secreted protein found only in vertebrates. ccbe1 was identified as a novel lymphangiogenic factor by a forward genetic screen in zebrafish for mutants lacking the thoracic duct. Human mutations in CCBE1 were subsequently found to cause Hennekam syndrome, a rare disorder characterized by lymphatic vessel malformations and mental retardation (OMIM 235510). However, only about 25% of Hennekam syndrome patients exhibit CCBE1 mutations, suggesting that the disorder may also arise from mutations in additional genes that function in a common pathway, e.g. a receptor for secreted CCBE1, and/or downstream signaling molecules {Alders, 2009 #2125}. However, CCBE1 has no homologue known to function in the blood vascular system and no molecular information regarding CCBE1 signaling pathways exists currently.

    To define the biological role of CCBE1 and compare it to VEGFC, the only other known lymphangiogenic factor, we have generated reporter mice and mice carrying conditional alleles for both genes. Analyses of these animals in combination with cellular and biochemical studies are under way to understand the mechanism by which CCBE1 regulates lymphatic vessel growth.

Blood Vascular Biology

We are actively investigating a number of signaling pathways that regulate blood vessel growth, with an emphasis on more recently discovered pathways that are known to cause human disease.

  • Cerebral Cavernous Malformation (CCM) signaling

    CCMs are thin-walled, dilated blood vessels in the brain that cause stroke and seizures. Positional cloning studies have identified loss of function mutations in 3 genes, CCM1 (aka KRIT1), CCM2 and CCM3 (aka PDCD10), as the cause of this disease. Biochemical studies have established that these intracellular proteins form a single signaling complex, and genetic studies in zebrafish, mice and humans have established that this pathway is required for both vessel development and integrity. The hypothesis that CCM signaling regulates endothelial junctions has emerged from studies of animal models, human CCMs and in vitro endothelial cells, but precisely how CCM signaling regulates vascular development and how its loss results in CCM formation remain unclear.

    We have found that the HEG receptor, expressed selectively in endothelial cells, nucleates the CCM signaling complex and interacts genetically with CCM1/2/3 during vascular development. HEG-deficiency confers cardiovascular integrity defects in mice, consistent with a role for this pathway in maintaining vascular integrity, as well as defects in both blood and lymphatic vessel formation. Using recently developed conditional mice we have confirmed that HEG-CCM signaling functions in an endothelial cell autonomous pathway.

    Our zebrafish studies have defined the GCK-III family of serine/threonine kinases as essential downstream effectors of HEG-CCM signaling during early cardiovascular development, but whether these proteins function in the CCM disease pathway is not yet known.

    Most recently, we have identified a novel component of the CCM pathway, a CCM2 homologue termed CCM2L, that is expressed selectively in angiogenic endothelial cells and binds CCM1 but not CCM3. Biochemical studies, mouse genetic studies and in vitro EC studies reveal that CCM2L is an endothelial-specific negative regulator of CCM2. These studies suggest that the CCM pathway is actively regulated to balance cardiovascular growth vs. stability and ongoing studies will investigate the downstream effectors that balance these two arms of the CCM signaling pathway.

  • Regulation of vascular function by fluid shear forces

    Fluid forces generated by pulsatile beating of the heart are intrinsic to the blood vascular system. Hemodynamic forces regulate blood pressure and oxygen delivery, and atherosclerotic plaques develop preferentially at vascular sites lacking laminar fluid shear forces in humans and mice. Although the contribution of hemodynamic forces to vascular physiology and disease has been evident for over a century, the molecular and genetic basis for these responses remains almost entirely unknown. Identification of the signaling pathways that couple fluid forces to vascular responses is particularly relevant to coronary artery disease since the greatest variations in shear forces exist within coronary vessels, and are magnified at sites of atherosclerotic narrowing.

    Our studies to understand these responses have focused on Kruppel-like factor 2 (KLF2), an endothelial transcription factor that we have identified as an essential mediator of hemodynamic responses in vivo. More recently we have described a natural model of vascular malformation, the SLP76-deficient mouse, in which blood flow reprograms lymphatic vessels to blood vessels.


  • Mark Kahn, MD
  • Yiqing Yang, PhD
  • Wei Pan, PhD
  • Zinan Zhou
    PhD Student
  • Lauren Goddard, PhD
  • Beth Lubeck, PhD
  • Daniel Sweet, PhD
  • Hung Manh Bui
    PhD Student
  • Mei Chen, BS
  • Jeremy Chang, BS
    MS Student
  • Patricia Mericko-Ishizuka, MS

Selected Publications

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