Vascular development consists of two phases: vasculogenic creation of vessels by endothelial progenitor cells and subsequent angiogenic remodeling of existing vessels. Mice lacking the hematopoietic signaling protein Slp-76 develop a vascular phenotype in which nascent lymphatic vessels connect to preexisting blood vessels. Our studies of the cell type responsible for this vascular phenotype suggest that Slp-76 is required in hematopoietic endothelial progenitor cells and not in mature endothelial cells. Remarkably, blood-lymphatic connections are corrected during later lymphatic remodeling, leaving surviving animals with arterio-venous shunts in which mesenteric lymphatics carry blood. These congenital lymphatics subsequently lose lymphatic identity, suggesting that fluid flow forces are sufficient for the molecular reprogramming of lymphatic vessel identity in vivo. These observations lead us to hypothesize that an early vasculogenic phase of lymphatic growth utilizes hematopoietic endothelial progenitors while lymphatic vessels can be remodeled and even alter their vessel identity in response to blood flow during later angiogenic phases of vessel growth. In the present proposal we will test these hypotheses and address the nature of the molecular defect by which loss of Slp-76 confers vascular mixing.
Our specific aims i nclude:
Aim 1. To determine the contribution of hematopoietic cells to developing lymphatic endothelium using genetic lineage tracing.
Aim 2. To test the role of Slp-76 in the maturation and function of endothelial progenitors.
Aim 3. To determine if fluid shear forces alter lymphatic endothelial identity. These studies will shed light on the basic mechanisms of lymphatic vascular development, the use of hematopoietic cells as endothelial progenitors, and the role of blood flow in establishing vessel identity.This proposal will investigate a new pathway by which blood cells contribute to the formation of lymphatic vessels. Lymphatic vessels are needed to remove fluid from tissues and edema secondary to lymphatic vascular insufficiency is a common side effect of radiation treatment and infectious diseases. These studies are therefore relevant to the development of new ways to treat of lymphatic vascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL072798-07
Application #
7580953
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Gao, Yunling
Project Start
2003-04-01
Project End
2012-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
7
Fiscal Year
2009
Total Cost
$393,750
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Boulaftali, Yacine; Hess, Paul R; Kahn, Mark L et al. (2014) Platelet immunoreceptor tyrosine-based activation motif (ITAM) signaling and vascular integrity. Circ Res 114:1174-84
Boulaftali, Yacine; Hess, Paul R; Getz, Todd M et al. (2013) Platelet ITAM signaling is critical for vascular integrity in inflammation. J Clin Invest 123:908-16
Chen, Chiu-Yu; Bertozzi, Cara; Zou, Zhiying et al. (2012) Blood flow reprograms lymphatic vessels to blood vessels. J Clin Invest 122:2006-17
Schmaier, Alec A; Stalker, Timothy J; Runge, Jeffrey J et al. (2011) Occlusive thrombi arise in mammals but not birds in response to arterial injury: evolutionary insight into human cardiovascular disease. Blood 118:3661-9
Bertozzi, Cara C; Hess, Paul R; Kahn, Mark L (2010) Platelets: covert regulators of lymphatic development. Arterioscler Thromb Vasc Biol 30:2368-71
Bertozzi, Cara C; Schmaier, Alec A; Mericko, Patricia et al. (2010) Platelets regulate lymphatic vascular development through CLEC-2-SLP-76 signaling. Blood 116:661-70
Abtahian, Farhad; Bezman, Natalie; Clemens, Regina et al. (2006) Evidence for the requirement of ITAM domains but not SLP-76/Gads interaction for integrin signaling in hematopoietic cells. Mol Cell Biol 26:6936-49
Sebzda, Eric; Hibbard, Chris; Sweeney, Shawn et al. (2006) Syk and Slp-76 mutant mice reveal a cell-autonomous hematopoietic cell contribution to vascular development. Dev Cell 11:349-61