The Notch signaling pathway in retinal dysplasia and retina vascular homeostasis

The retina is one of the most essential elements of vision pathway in vertebrate. The dysplasia of retina cause congenital blindness or vision disability in individuals, and the misbalance in adult retinal vascular homeostasis leads to neo adults, such as diabetic retinopathy or age-related macular degeneration. Many developmental signaling pathways are involved in the process of retinal development and vascular homeostasis. Among them, Notch signaling pathway has long been studied, and Notch signaling-interfered mouse models show both neural retina dysplasia and vascular abnormality. In this review, we discuss the roles of Notch signaling in the maintenance of retinal progenitor cells, specification of retinal neurons and glial cells, and the sustaining of retina vascular homeostasis, especially from the aspects of conditional knockout mouse models. The potential of Notch signal manipulation may provide a powerful cell fate- and neovascularization-controUing tool that could have important applications in treatment of retinal diseases.

The FGF21-adiponectin axis in controlling energy and vascular homeostasis

Whole-body energy metabolism and cardiovascular homeostasis are tightly controlled processes that involve highly coordinated crosstalk among distal organs.This is mainly achieved by a large number of hormones released from each organ.Among them,fibroblast growth factor 21(FGF21)and adiponectin have recently gained considerable attention,since both of them possess multiple profound protective effects against a myriad of cardio-metabolic disorders.Despite their distinct structuresand production sites,these two hormones share striking functional similarity.This dichotomy is recently reconciled by the demonstration of the FGF21-adiponectin axis.In adipocytes,both transcription and secretion of adiponectin are strongly induced by FGF21,which is partially dependent on PPARg activity.Furthermore,the glucose-lowering,lipid-clearing,and anti-atherosclerotic functions of FGF21 are diminished in adiponectin-null mice,suggesting that adiponectin serves as an obligatory mediator of FGF21-elicited metabolic and vascular benefits.However,in both animals and human subjects with obesity,circulating FGF21 levels are increased whereas plasma adiponectin concentrations are reduced,perhaps due to FGF21 resistance,suggesting that dysfunctional FGF21-adiponectin axis is an important contributor to the pathogenesis of obesity-related cardio-metabolic syndrome.The FGF21-adiponectin axis protects against a cluster of cardio-metabolic disorders via mediating multi-organ communications,and is a promising target for therapeutic interventions of these chronic diseases.

Mechanistic perspectives of calorie restriction on vascular homeostasis

Calorie restriction(CR)is a dietary regime based on low calorie intake.CR without malnutrition extends lifespan in a wide range of organisms from yeast to rodents,and CR can prevent and delay the onset of age-related functional decline and diseases in human and non-human primates.CR is a safe and effective intervention to reduce vascular risk factors in humans.In recent years,studies in rodents have provided mechanistic insights into the beneficial effects of CR on vascular homeostasis,including reduced oxidative stress,enhanced nitric oxide(NO)bioactivity,and decreased inflammation.A number of important molecules,including sirtuins,AMP-activated protein kinase,mammalian targets of rapamycin,endothelial nitric oxidase and their regulatory pathways are involved in the maintenance of vascular homeostasis.Evidence has shown that these pathways are responsible for many aspects of CR’s effects,and that they may also mediate the effects of CR on vasculature.

Urgent call for reconsideration of chronic kidney disease

Circulating toxins namely： free radicals, cytokines and metabolic products induce glomerular endothelial dys-function, hemodynamic maladjustment and chronic ischemic state;this leads to tubulointerstitial fbrosis in chronic kidney disease （CKD）. Altered vascular homeo-stasis observed in late stage CKD revealed defective angiogenesis and impaired nitric oxide production ex-plaining therapeutic resistance to vasodilator treatment in late stage CKD. Under current practice, CKD patients are diagnosed and treated at a rather late stage due to the lack of sensitivity of the diagnostic markers avail-able. This suggests the need for an alternative thera-peutic strategy implementing the therapeutic approachat an early stage. This view is supported by the normal or mildly impaired vascular homeostasis observed in early stage CKD. Treatment at this early stage can potentially enhance renal perfusion, correct the renal ischemic state and restore renal function. Thus, this alternative therapeutic approach would effectively pre-vent end-stage renal disease.

Red Onion (Allium Cepa L.) Methanolic Extract Increases Extracellular Nucleotide Hydrolysis in Rat Serum

Ectonucleotidases are enzymes involved in nucleotides metabolism. The amount of circulating nucleotides may modulate distinct pathophysiological processes in the vasculature, including platelet aggregation and vascular tone. Onion (Allium cepa L.) phenolic compounds modulate enzymatic activity. The present study evaluated the total phenolic content of red onion methanolic extract, its antioxidant capacity, and its ability to interfere in nucleotides hydrolyses in rat serum. Total phenolic content was determined with the Folin-Ciocalteau reagent using gallic acid as a standard, while total flavonoid content was obtained through the aluminum chloride colorimetric method with quercetin as a standard. Antioxidant capacity was evaluated from the ability of the extract to scavenge ABTS·+ and DPPH· radicals. ATP, ADP, AMP, and p-Nph-5'-TMP hydrolyses were colorimetrically determined in response to different onion extract concentrations (0, 125, 250, 500, or 1000 μg/mL). Phenolic content of the extract was 54.35 mg GAE 100 g-1 sample, while flavonoid content was 7.22 mg quercetin g-1 sample. The IC50 value for ABTS·+ was 374.13 ± 7.52 μg/mL, while it was 440.29 ± 15.17 μg/mL for DPPH·. Red onion extract increased ADP and p-Nph-5'-TMP hydrolysis. The results confirmed that red onion contains high content of antioxidant, mainly flavonoids, and high antioxidant capacity. Additionally, biochemical studies suggest that the increased ADP breakdown may be important to regulate vascular processes. As it occurs for other enzymes, the antioxidant capacity of onion extract may neutralize reactive oxygen species (ROS) formation and favor ectonucleotidase activity and the hydrolysis of ADP, a major platelet agonist.

Notch signaling in blood vessels: from morphogenesis to homeostasis

Notch signaling is an evolutionarily conserved intercellular signaling pathway that plays numerous crucial roles in vascular development and physiology.Compelling evidence indicates that Notch signaling is vital for vascular morphogenesis including arterial and venous differentiation and endothelial tip and stalk cell specification during sprouting angiogenesis and also vessel maturation featured by mural cell differentiation and recruitment.Notch signaling is also required for vascular homeostasis in adults by keeping quiescent phalanx cells from re-entering cell cycle and by modulating the behavior of endothelial progenitor cells.We will summarize recent advances of Notch pathway in vascular biology with special emphasis on the underlying molecular mechanisms.

Mechanistic insight into lysyl oxidase in vascular remodeling and angiogenesis

Vascular remodeling and angiogenesis are two key processes in the maintenance of vascular homeostasis and involved in a wide array of vascular pathologies. Following these processes, extracellular matrix (ECM) provides the mechanical foundation for vascular walls. Lysyl oxidase (LOX), the key matrix-modifying enzyme, has been demonstrated to significantly affect structural abnormality and dysfunction in the blood vessels. The role of LOX in vascular remodeling and angiogenesis has always been the subject in the current medical research. Therefore, we presently make a summarization of the biosynthesis of LOX and the mechanisms involved in vascular remodeling and angiogenesis, as well as the role of LOX in diseases associated with vascular abnormalities and the therapeutic potential via targeting LOX. In particular, we give a proposal that LOX likely reshapes matrisome-associated genes expressions in the regulation of vascular remodeling and angiogenesis, which serves as a mechanistic insight into the critical role of LOX in these two aspects. Additionally, LOX has also dual effects on the vascular dysfunction, namely, inhibition of LOX for improving hypertension, restenosis and malignant tumor while activation of LOX for curing arterial aneurysm and dissection. LOX-targeted therapy may provide a promising therapeutic strategy for the treatment of various vascular pathologies associated with vascular remodeling and angiogenesis.