title: Coronary vasculature patterning requires a novel endothelial ErbB2 holoreceptor.
abstract: Organogenesis and regeneration require coordination of cellular proliferation, regulated in part by secreted growth factors and cognate receptors, with tissue nutrient supply provided by expansion and patterning of blood vessels. Here we reveal unexpected combinatorial integration of a growth factor co-receptor with a heterodimeric partner and ligand known to regulate angiogenesis and vascular patterning. We show that ErbB2, which can mediate epidermal growth factor (EGF) and neuregulin signalling in multiple tissues, is unexpectedly expressed by endothelial cells where it partners with neuropilin 1 (Nrp1) to form a functional receptor for the vascular guidance molecule semaphorin 3d (Sema3d). Loss of Sema3d leads to improper patterning of the coronary veins, a phenotype recapitulated by endothelial loss of ErbB2. These findings have implications for possible cardiovascular side-effects of anti-ErbB2 therapies commonly used for cancer, and provide an example of integration at the molecular level of pathways involved in tissue growth and vascular patterning.
authors.affiliation: Department of Cell and Developmental Biology, Penn Cardiovascular Institute, Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Haig
authors.initials: H
authors.lastname: Aghajanian
authors.affiliation: Department of Cell and Developmental Biology, Penn Cardiovascular Institute, Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Department of Pediatrics, Chonnam National University Medical School, Gwangju 61186, South Korea.
authors.forename: Young Kuk
authors.initials: YK
authors.lastname: Cho
authors.affiliation: Department of Cell and Developmental Biology, Penn Cardiovascular Institute, Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Lauren J
authors.initials: LJ
authors.lastname: Manderfield
authors.affiliation: Department of Cell and Developmental Biology, Penn Cardiovascular Institute, Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Madison R
authors.initials: MR
authors.lastname: Herling
authors.affiliation: Department of Cell and Developmental Biology, Penn Cardiovascular Institute, Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Mudit
authors.initials: M
authors.lastname: Gupta
authors.affiliation: Department of Cell and Developmental Biology, Penn Cardiovascular Institute, Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Vivienne C
authors.initials: VC
authors.lastname: Ho
authors.affiliation: Department of Cell and Developmental Biology, Penn Cardiovascular Institute, Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Degenhardt
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Alla
authors.initials: A
authors.lastname: Aharonov
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Eldad
authors.identifier: 0000-0002-5212-9426
authors.initials: E
authors.lastname: Tzahor
authors.affiliation: Department of Cell and Developmental Biology, Penn Cardiovascular Institute, Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Epstein
mesh_terms: D000818:Animals; D003330:Coronary Vessel Anomalies / Q000235:genetics* / Q000378:metabolism; D003331:Coronary Vessels / Q000196:embryology*; D042783:Endothelial Cells / Q000378:metabolism*; D051379:Mice; D009024:Morphogenesis; D018919:Neovascularization, Physiologic; D039942:Neuropilin-1 / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D039961:Semaphorins / Q000378:metabolism*
chemical_list: D039942:Neuropilin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D039961:Semaphorins; C530499:Sema 3D protein, mouse; C524056:Erbb2 protein, mouse