Vascular Mural Cells Promote Noradrenergic Differentiation of Embryonic Sympathetic Neurons

The sympathetic nervous system controls smooth muscle tone and heart rate in the cardiovascular system. Postganglionic sympathetic neurons (SNs) develop in close proximity to the dorsal aorta (DA) and innervate visceral smooth muscle targets. Here, we use the zebrafish embryo to ask whether the DA is required for SN development. We show that noradrenergic (NA) differentiation of SN precursors temporally coincides with vascular mural cell (VMC) recruitment to the DA and vascular maturation. Blocking vascular maturation inhibits VMC recruitment and blocks NA differentiation of SN precursors. Inhibition of platelet-derived growth factor receptor (PDGFR) signaling prevents VMC differentiation and also blocks NA differentiation of SN precursors. NA differentiation is normal in cloche mutants that are devoid of endothelial cells but have VMCs. Thus, PDGFR-mediated mural cell recruitment mediates neurovascular interactions between the aorta and sympathetic precursors and promotes their noradrenergic differentiation

Studying vascular angiogenesis and senescence in zebrafish embryos

The zebrafish is an excellent animal model to study the formation of the vertebrate vascular network. The small size, the optical translucency, and the ability to model endothelial-specific fl uorescent transgenic lines in the zebrafish embryo had facilitate, in the past 10 years, the direct visualization of vessels formation and remodeling. Furthermore, zebrafish is an excellent disease model such as for cancer and neurodegenerative diseases. Cerebral amyloid angiopathy (CAA) is a human neurovascular degenerative disease, caused by Amyloid β (Aβ) peptides deposition around brain microvessels, and characterized by vascular brain degenerative changes. By using the zebrafish model, we investigated the effect of Aβ peptides treatment in vessel formation during embryogenesis. We showed that the defects in the vascular remodeling and senescence can be detected, respectively, via staining for alkaline phosphatase activity and β-galactosidase or cyclindependent kinase inhibitor p21 expression. We demonstrated that treating zebrafish embryos with these oxidative peptides reduces angiogenesis and promotes premature vascular senescence. In this chapter, we will describe the methods to reveal both angiogenesis and senescence defects upon Aβ peptides treatment of the zebrafish embryos

Chapter 2. Antiangiogenic drugs: Chemosensitizers for combination cancer therapy

Angiogenesis is a key step in tumor progression and recurrence, and is known as a hallmark of solid tumors. The architecture of the tumor vasculature is deregulated, vessels are immature, and their functionality is defective, causing increase of interstitial pressure, hypoxia and acidity in the tumor microenvironment, and favouring an enhanced tumor dissemination and metastasis. The defective tumor vasculature as well as the modifications of tumor microenvironment are a barrier for the effective delivery and accumulation of either the anti-cancer drugs, including anti-angiogenic drugs, or immune competent T cells in tumor area, thus promoting tumor resistance to therapy. Among the various approaches for targeting tumor angiogenesis, vascular normalization and vessel maturation are considered the most promising approaches, which favour both an effective delivery of anticancer drugs and accumulation of immune competent T cells into the tumor area. Antiangiogenic therapy can downregulate continuous angiogenic signalling and result in vascular normalization, such as pruning, vascular maturation, and increased perfusion. Thus, antiangiogenic drugs are now considered promising chemosensitizers of anti-cancer strategies such as chemotherapy, target therapies and immune checkpoint inhibitors in several advanced tumors. This review summarizes the current understanding and clinical development of combination therapy with anti-angiogenic drugs and anticancer chemo-, targeted- and immune-therapies

Amyloid-β Precursor Protein APP Down-Regulation Alters Actin Cytoskeleton-Interacting Proteins in Endothelial Cells

The amyloid-β precursor protein (APP) is a ubiquitous membrane protein often associated with Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). Despite its role in the development of the pathogenesis, APP exerts several physiological roles that have been mainly investigated in neuronal tissue. To date, the role of APP in vasculature and endothelial cells has not been fully elucidated. In this study, we used molecular and proteomic approaches to identify and investigate major cellular targets of APP down-regulation in endothelial cells. We found that APP is necessary for endothelial cells proliferation, migration and adhesion. The loss of APP alters focal adhesion stability and cell–cell junctions’ expression. Moreover, APP is necessary to mediate endothelial response to the VEGF-A growth factor. Finally, we document that APP propagates exogenous stimuli and mediates cellular response in endothelial cells by modulating the Scr/FAK signaling pathway. Thus, the intact expression and processing of APP is required for normal endothelial function. The identification of molecular mechanisms responsible for vasoprotective properties of endothelial APP may have an impact on clinical efforts to preserve and protect healthy vasculature in patients at risk of the development of cerebrovascular disease and dementia including AD and CAA

Common Protective Strategies in Neurodegenerative Disease: Focusing on Risk Factors to Target the Cellular Redox System

Neurodegenerative disease is an umbrella term for different conditions which primarily affect the neurons in the human brain. In the last century, significant research has been focused on mechanisms and risk factors relevant to the multifaceted etiopathogenesis of neurodegenerative diseases. Currently, neurodegenerative diseases are incurable, and the treatments available only control the symptoms or delay the progression of the disease. This review is aimed at characterizing the complex network of molecular mechanisms underpinning acute and chronic neurodegeneration, focusing on the disturbance in redox homeostasis, as a common mechanism behind five pivotal risk factors: aging, oxidative stress, inflammation, glycation, and vascular injury. Considering the complex multifactorial nature of neurodegenerative diseases, a preventive strategy able to simultaneously target multiple risk factors and disease mechanisms at an early stage is most likely to be effective to slow/halt the progression of neurodegenerative diseases

Data from: MHC genotype predicts mate choice in the ring-necked pheasant Phasianus colchicus

Females of several vertebrate species selectively mate with males on the basis of the major histocompatibility complex (MHC) genes. As androgen-mediated maternal effects have long-lasting consequences for the adult phenotype, both mating and reproductive success may depend on the combined effect of MHC genotype and exposure to androgens during early ontogeny. We studied how MHC-based mate choice in ring-necked pheasants (Phasianus colchicus) was influenced by an experimental in ovo testosterone (T) increase. There was no conclusive evidence of in ovo T treatment differentially affecting mate choice in relation to MHC genotype. However, females avoided mating with males with a wholly different MHC genotype compared with males sharing at least one MHC allele. Females also tended to avoid mating with MHC-identical males, though not significantly so. These findings suggest that female pheasants preferred males with intermediate MHC dissimilarity. Male MHC heterozygosity or diversity did not predict the expression of ornaments or male dominance rank. Thus, MHC-based mating preferences in the ring-necked pheasant do not seem to be mediated by ornaments’ expression and may have evolved mainly to reduce the costs of high heterozygosity at MHC loci for the progeny, such as increased risk of autoimmune diseases or disruption of coadapted gene pools

Behaviour

This file contains the number of copulations of each male-female pair, alongside with different metrics of MHC genotype (distances or similarity between mating partners, different categorizations of MHC genotype

Phenotypic traits

This file contains data of phenotypic traits and MHC genotype of ring-necked pheasant males included in the stud