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.
Highlights
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
We examined the hearts of postnatal semaphorin 3d (Sema3d) À / À mice to investigate the effects of Sema3d on the development of the coronary vasculature
In this study, we provide evidence for an unexpected role for ErbB2 in venous endothelial cells where it can partner with Nrp[1] to form a receptor for the repellent guidance molecule Sema3d (Fig. 5f)
Summary
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. 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). A number of studies have identified various sources of the endothelial cells that give rise to the coronary arterial and venous vasculature including the proepicardium[4], epicardium, endocardium and sinus venosus[5,6] Cells migrating from these sources form tubular structures and a primary vascular plexus surrounding the heart. During this time, the arterial vascular tubes around the aortic trunk penetrate the aorta, while the venous capillary beds form connections with the coronary sinus allowing for circulation of blood through the coronary vessels. ErbB2 expression is well characterized in myocardium[17] and plays a critical role in cardiomyocyte proliferation and differentiation during development[18,19], a role in endothelial function has yet to be described
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call