Anomalous pulmonary venous return is a common form of congenital heart disease though little is known about how the pulmonary veins are normally patterned. Semaphorins are guidance molecules that mediate repulsive cues for axons and blood vessels. We have generated two distinct null alleles of a poorly studied class III semaphorin, sema3d, which results in anomalous pulmonary venous return. Our data suggests that sema3d normally functions as a boundary, constraining migration of nascent pulmonary venous endothelium. The absence of sema3d allows for ectopic migration and patterning of pulmonary venous endothelial cells, leading to anomalous connections. These findings provide an altogether new description of the developmental cause of anomalous pulmonary veins that demands revision of common textbook explanations. In this proposal, we will test the hypothesis that sema3d binds directly to pulmonary venous endothelial cells causing repulsion. We will identify the functional sema3d receptor and the intracellular signaling pathways that result in repulsion, and we will examine how sema3d functionally interacts with Notch and Vegf during angiogenesis.

Public Health Relevance

These studies address the genetic and mechanistic cause of a common form of congenital heart disease in which the pulmonary veins, returning blood from the lungs to the heart, connect to the wrong heart chamber. These studies will identify candidate genes for the cause of this disorder. Our work shows that vascular guidance molecules help to normally pattern the pulmonary veins, and these factors might be useful as therapeutic agents that affect the growth and patterning of blood vessels in diseases such as cancer.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HL118768-02
Application #
8705007
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Aghajanian, Haig; Choi, Connie; Ho, Vivienne C et al. (2014) Semaphorin 3d and semaphorin 3e direct endothelial motility through distinct molecular signaling pathways. J Biol Chem 289:17971-9
Worzfeld, Thomas; Swiercz, Jakub M; Sentürk, Aycan et al. (2014) Genetic dissection of plexin signaling in vivo. Proc Natl Acad Sci U S A 111:2194-9