The neuropilin (Nrp) family are essential multifunctional vertebrate cell surface receptors. Nrps were initially characterized as receptors for class III Semaphorin (Sema3) family members, functioning in axon guidance. Nrps have also been shown to be critical for Vascular Endothelial Growth Factor (VEGF) dependent angiogenesis. Intriguingly, recent data show that Nrp function in these seemingly divergent pathways is critically determined by ligand-mediated cross-talk, which underlies Nrp function in both physiological and pathological processes. In addition to functioning in these two pathways, Nrps have been shown to specifically function in a number of other fundamental signaling pathways as well. Multiple general mechanisms have been found to directly contribute to the pleiotropic function of Nrp. Here we review critical general features of Nrps function as essential receptors integrating multiple molecular cues into diverse cellular signaling.

SUMMARY Vascular endothelial growth factor-C (VEGF-C) is a potent lymphangiogenic cytokine that signals via the coordinated action of two cell surface receptors, Neuropilin-2 (Nrp2) and VEGFR-3. Diseases associated with both loss and gain of VEGF-C function, lymphedema and cancer, respectively, motivate studies of VEGF-C/Nrp2 binding and inhibition. Here we demonstrate that VEGF-C binding to Nrp2 is regulated by C-terminal proteolytic maturation. The structure of the VEGF-C C-terminus in complex with the ligand-binding domains of Nrp2 demonstrates that a cryptic Nrp2 binding motif is released upon proteolysis, allowing specific engagement with the b1 domain of Nrp2. Based on the identified structural requirements for Nrp2 binding to VEGF-C, we hypothesized that the endogenous secreted splice form of Nrp2, s9Nrp2, may function as a selective inhibitor of VEGF-C. We find that s9Nrp2 forms a stable dimer that potently inhibits VEGF-C/Nrp2 binding and cellular signaling. These data provide critical insight into VEGF-C/Nrp2 binding and inhibition.

Background: Implant based breast reconstruction is the most common method of breast reconstruction in the United States but the outcomes of subsequent implant based reconstruction after a tissue expander (TE) complication are rarely studied. The purpose of this study is to determine the long term incidence of implant loss in patents with a previous TE complication. Methods: This is a retrospective review of the long term outcomes of all patients with TE complications at a large academic medical center from 2003–2013. Patients with subsequent TE or implant complications were compared to those with no further complications to assess risk factors for additional complications, or reconstructive failure. Results: One hundred sixty-two women were included in this study. The mean follow up was 8.3 ± 3.1 years. Forty-eight women (30%) went on to have a second TE or implant placed. They did not differ from women who went on to autologous reconstruction or no further reconstruction. Of these, 34 women (71%) had no further complications, and 38 women (79%) had a successful implant based reconstruction at final follow-up. There were no patient or surgical factors significantly associated with a second complication or implant loss. Conclusions: Following TE complications, it is reasonable to offer women a second attempt at tissue expansion and implant placement. This study demonstrates that long term success rates are high and there are no definitive patient or surgical factors that preclude a second attempt at implant based breast reconstruction.