Background: The adherens protein VE-cadherin has diverse roles in organ-specific lymphatic vessels. However, its physiological role in cardiac lymphatics and its interaction with lymphangiogenic factors, has not been fully explored. We sought to determine the spatio-temporal functions of VE-cadherin in cardiac lymphatics and mechanistically elucidate how VE-cadherin loss influences pro-lymphangiogenic signaling pathways, such as adrenomedullin (AM) and VEGF-C/VEGFR3 signaling. Methods: Cdh5 flox/flox ;Prox1CreER T2 mice were used to delete VE-cadherin in lymphatic endothelial cells (LECs) across life stages, including embryonic, postnatal and adult. Lymphatic architecture and function was characterized utilizing immunostaining and functional lymphangiography. To evaluate the impact of temporal and functional regression of cardiac lymphatics in Cdh5 flox/flox ;Prox1CreER T2 mice, left anterior descending artery ligation was performed and cardiac function and repair after myocardial infarction was evaluated by echocardiography and histology. Cellular effects of VE-cadherin deletion on lymphatic signaling pathways were assessed by knock-down of VE-cadherin in cultured LECs. Results: Embryonic deletion of VE-cadherin produced edematous embryos with dilated cardiac lymphatics with significantly altered vessel tip morphology. Postnatal deletion of VE-cadherin caused complete disassembly of cardiac lymphatics. Adult deletion caused a temporal regression of the quiescent epicardial lymphatic network which correlated with significant dermal and cardiac lymphatic dysfunction, as measured by fluorescent and quantum dot lymphangiography, respectively. Surprisingly, despite regression of cardiac lymphatics, Cdh5 flox/flox ;Prox1CreER T2 mice exhibited preserved cardiac function, both at baseline and following myocardial infarction, compared to control mice. Mechanistically, loss of VE-cadherin leads to aberrant cellular internalization of VEGFR3, precluding the ability of VEGFR3 to be either canonically activated by VEGF-C or non-canonically transactivated by AM signaling, impairing downstream processes such as cellular proliferation. Conclusions: VE-cadherin is an essential scaffolding protein to maintain pro-lymphangiogenic signaling nodes at the plasma membrane, which are required for the development and adult maintenance of cardiac lymphatics, but not for cardiac function basally or after injury.

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The vomeronasal system (VNS) is specialized in the detection of salient chemical cues triggering social and neuroendocrine responses. Such responses are not always stereotyped, instead, they vary depending on age, sex, and reproductive state, yet the mechanisms underlying this variability are unclear. Here, by analyzing neuronal survival in the first processing nucleus of the VNS, namely the accessory olfactory bulb (AOB), through multiple bromodeoxyuridine birthdating protocols, we show that exposure of female mice to male soiled bedding material affects the integration of newborn granule interneurons mainly after puberty. This effect is induced by urine compounds produced by mature males, as bedding soiled by younger males was ineffective. The granule cell increase induced by mature male odor exposure is not prevented by pre-pubertal ovariectomy, indicating a lesser role of circulating estrogens in this plasticity. Interestingly, the intake of adult male urine-derived cues by the female vomeronasal organ increases during puberty, suggesting a direct correlation between sensory activity and AOB neuronal plasticity. Thus, as odor exposure increases the responses of newly born cells to the experienced stimuli, the addition of new GABAergic inhibitory cells to the AOB might contribute to the shaping of vomeronasal processing of male cues after puberty. Consistently, only after puberty, female mice are capable to discriminate individual male odors through the VNS.

The lymphatic system has received increasing scientific and clinical attention because a wide variety of diseases are linked to lymphatic pathologies and because the lymphatic system serves as an ideal conduit for drug delivery. Lymphatic vessels exert heterogeneous roles in different organs and vascular beds, and consequently, their dysfunction leads to distinct organ-specific outcomes. Although studies in animal model systems have led to the identification of crucial lymphatic genes with potential therapeutic benefit, effective lymphatic-targeted therapeutics are currently lacking for human lymphatic pathological conditions. Here, we focus on the therapeutic roles of lymphatic vessels in diseases and summarize the promising therapeutic targets for modulating lymphangiogenesis or lymphatic function in preclinical or clinical settings. We also discuss considerations for drug delivery or targeting of lymphatic vessels for treatment of lymphatic-related diseases. The lymphatic vasculature is rapidly emerging as a critical system for targeted modulation of its function and as a vehicle for innovative drug delivery.

Wilbrand and Saenger 1 studied optic chiasms after unilateral enucleation, noting inferonasal crossing fibers curved anteriorly into the contralateral optic nerve (Wilbrand knee; figure, A). This explains contralateral superotemporal visual field defects (junctional scotomas) with optic nerve lesions at the chiasmal junction. However, Wilbrand knee may be an enucleation artifact.2 The anisotropic light-reflecting properties of myelinated axons permitted imaging of normal human chiasms. Thin sections (25 mm) were illuminated and digitally imaged from 3 incident angles. Each of the images was pseudocolored (red, green, or blue) and merged, revealing an anomalously oriented fiber tract (appearing white) that reversed direction at the optic nerve-chiasm junction, found in inferior (figure, C) but not in superior sections (figure, B), consistent with Wilbrand and Saenger's original description.