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author:("arrive, Bruno")
1.  Netrin-1 controls sympathetic arterial innervation 
The Journal of Clinical Investigation  2014;124(7):3230-3240.
Autonomic sympathetic nerves innervate peripheral resistance arteries, thereby regulating vascular tone and controlling blood supply to organs. Despite the fundamental importance of blood flow control, how sympathetic arterial innervation develops remains largely unknown. Here, we identified the axon guidance cue netrin-1 as an essential factor required for development of arterial innervation in mice. Netrin-1 was produced by arterial smooth muscle cells (SMCs) at the onset of innervation, and arterial innervation required the interaction of netrin-1 with its receptor, deleted in colorectal cancer (DCC), on sympathetic growth cones. Function-blocking approaches, including cell type–specific deletion of the genes encoding Ntn1 in SMCs and Dcc in sympathetic neurons, led to severe and selective reduction of sympathetic innervation and to defective vasoconstriction in resistance arteries. These findings indicate that netrin-1 and DCC are critical for the control of arterial innervation and blood flow regulation in peripheral organs.
PMCID: PMC4071369  PMID: 24937433
2.  ALK1 Signaling Inhibits Angiogenesis by Cooperating with the Notch Pathway 
Developmental cell  2012;22(3):489-500.
Activin receptor-like kinase 1 (ALK1) is an endothelial-specific member of the TGF-β/BMP receptor family that is inactivated in patients with hereditary hemorrhagic telangiectasia (HHT). How ALK1 signaling regulates angiogenesis remains incompletely understood. Here we show that ALK1 inhibits angiogenesis by cooperating with the Notch pathway. Blocking Alk1 signaling during postnatal development in mice leads to retinal hypervascularization and the appearance of arteriovenous malformations (AVMs). Combined blockade of Alk1 and Notch signaling further exacerbates hypervascularization, whereas activation of Alk1 by its high-affinity ligand BMP9 rescues hypersprouting induced by Notch inhibition. Mechanistically, ALK1-dependent SMAD signaling synergizes with activated Notch in stalk cells to induce expression of the Notch targets HEY1 and HEY2, thereby repressing VEGF signaling, tip cell formation, and endothelial sprouting. Taken together, these results uncover a direct link between ALK1 and Notch signaling during vascular morpho-genesis that may be relevant to the pathogenesis of HHT vascular lesions.
PMCID: PMC4047762  PMID: 22421041
3.  Endothelial NFκB -Dependent Regulation of Arteriogenesis and Branching 
Circulation  2012;126(22):2589-2600.
Arteriogenesis and collateral formation are complex processes requiring integration of multiple inputs to coordinate vessel branching, growth, maturation and network size. Factors regulating these processes have not been determined.
Methods and Results
We used a dominant-negative IκBαSR construct under control of an endothelial-specific inducible promoter to selectively suppress endothelial NFκB activation during development or in the adult vasculature or in vitro. Inhibition of NFκB activation resulted in formation of an excessively branched arterial network that was composed of immature vessels and provided poor distal tissue perfusion. Molecular analysis demonstrated reduced adhesion molecules expression leading to decreased monocyte influx, reduced HIF-1α levels and a marked decrease in Dll4 expression with a consequent decrease in Notch signaling. The latter was the principal cause of increased vascular branching, as treatment with Jagged-1 peptide reduced the size of arterial network to baseline levels.
These findings identify NFκB as a key regulator of adult and developmental arteriogenesis and collateral formation. NFkB achieves this by regulating HIF1α-dependent expression of VEGF-A and PDGF-BB that are necessary for development and maturation of the arterial collateral network and by regulating Dll4 expression that in turn determines the network’s size and complexity.
PMCID: PMC3514045  PMID: 23091063
arteriogenesis; NFκB; HIF; Dll4
4.  Context Dependent Pro-Angiogenic Function of Bone Morphogenetic Protein Signaling is Mediated by Disabled Homolog 2 
Developmental cell  2012;23(2):441-448.
Bone Morphogenetic Proteins (BMPs) have diverse functions during development in vertebrates. We have recently shown that BMP2 signaling promotes venous specific angiogenesis in zebrafish embryos. However, factors that confer a context dependent pro-angiogenic function of BMP2 signaling within endothelial cells need to be identified. Here, we report that Disabled homolog 2 (Dab2), a cargo specific adaptor protein for Clathrin, is essential to mediate the pro-angiogenic function of BMP2 signaling. We find that inhibition of Dab2 attenuates internalization of BMP receptors and abrogates the pro-angiogenic effects of BMP signaling in endothelial cells. Moreover, inhibition of Dab2 decreases phosphorylation of SMAD-1, 5, and 8, indicating that Dab2 plays an essential role in determining the outcome of BMP signaling within endothelial cells, and may provide a molecular basis for a context dependent pro-angiogenic function of BMP2 signaling.
PMCID: PMC3659797  PMID: 22898784
5.  Neuropilin-2 mediates VEGF-C–induced lymphatic sprouting together with VEGFR3 
The Journal of Cell Biology  2010;188(1):115-130.
If neuropilin-2 and the growth factor VEGF-C don’t come together, lymphatic vessels don’t branch apart.
Vascular sprouting is a key process-driving development of the vascular system. In this study, we show that neuropilin-2 (Nrp2), a transmembrane receptor for the lymphangiogenic vascular endothelial growth factor C (VEGF-C), plays an important role in lymphatic vessel sprouting. Blocking VEGF-C binding to Nrp2 using antibodies specifically inhibits sprouting of developing lymphatic endothelial tip cells in vivo. In vitro analyses show that Nrp2 modulates lymphatic endothelial tip cell extension and prevents tip cell stalling and retraction during vascular sprout formation. Genetic deletion of Nrp2 reproduces the sprouting defects seen after antibody treatment. To investigate whether this defect depends on Nrp2 interaction with VEGF receptor 2 (VEGFR2) and/or 3, we intercrossed heterozygous mice lacking one allele of these receptors. Double-heterozygous nrp2vegfr2 mice develop normally without detectable lymphatic sprouting defects. In contrast, double-heterozygote nrp2vegfr3 mice show a reduction of lymphatic vessel sprouting and decreased lymph vessel branching in adult organs. Thus, interaction between Nrp2 and VEGFR3 mediates proper lymphatic vessel sprouting in response to VEGF-C.
PMCID: PMC2812843  PMID: 20065093
6.  Activated Notch4 Inhibits Angiogenesis: Role of β1-Integrin Activation 
Molecular and Cellular Biology  2002;22(8):2830-2841.
Notch4 is a member of the Notch family of transmembrane receptors that is expressed primarily on endothelial cells. Activation of Notch in various cell systems has been shown to regulate cell fate decisions. The sprouting of endothelial cells from microvessels, or angiogenesis, involves the modulation of the endothelial cell phenotype. Based on the function of other Notch family members and the expression pattern of Notch4, we postulated that Notch4 activation would modulate angiogenesis. Using an in vitro endothelial-sprouting assay, we show that expression of constitutively active Notch4 in human dermal microvascular endothelial cells (HMEC-1) inhibits endothelial sprouting. We also show that activated Notch4 inhibits vascular endothelial growth factor (VEGF)-induced angiogenesis in the chick chorioallantoic membrane in vivo. Activated Notch4 does not inhibit HMEC-1 proliferation or migration through fibrinogen. However, migration through collagen is inhibited. Our data show that Notch4 cells exhibit increased β1-integrin-mediated adhesion to collagen. HMEC-1 expressing activated Notch4 do not have increased surface expression of β1-integrins. Rather, we demonstrate that Notch4-expressing cells display β1-integrin in an active, high-affinity conformation. Furthermore, using function-activating β1-integrin antibodies, we demonstrate that activation of β1-integrins is sufficient to inhibit VEGF-induced endothelial sprouting in vitro and angiogenesis in vivo. Our findings suggest that constitutive Notch4 activation in endothelial cells inhibits angiogenesis in part by promoting β1-integrin-mediated adhesion to the underlying matrix.
PMCID: PMC133705  PMID: 11909975

Results 1-6 (6)