Fzd7 (Frizzled-7) Expressed by Endothelial Cells Controls Blood Vessel Formation Through Wnt/β-Catenin Canonical Signaling.

Abstract OBJECTIVE: Vessel formation requires precise orchestration of a series of morphometric and molecular events controlled by a multitude of angiogenic factors and morphogens. Wnt/frizzled signaling is required for proper vascular formation. In this study, we investigated the role of the Fzd7 (frizzled-7) receptor in retinal vascular development and its relationship with the Wnt/β-catenin canonical pathway and Notch signaling. APPROACH AND RESULTS: Using transgenic mice, we demonstrated that Fzd7 is required for postnatal vascular formation. Endothelial cell (EC) deletion of fzd7 (fzd7ECKO) delayed retinal plexus formation because of an impairment in tip cell phenotype and a decrease in stalk cell proliferation. Dvl (dishevelled) proteins are a main component of Wnt signaling and play a functionally redundant role. We found that Dvl3 depletion in dvl1-/- mice mimicked the fzd7ECKO vascular phenotype and demonstrated that Fzd7 acted via β-catenin activation by showing that LiCl treatment rescued impairment in tip and stalk cell phenotypes induced in fzd7 mutants. Deletion of fzd7 or Dvl1/3 induced a strong decrease in Wnt canonical genes and Notch partners' expression. Genetic and pharmacological rescue strategies demonstrated that Fzd7 acted via β-catenin activation, upstream of Notch signaling to control Dll4 and Jagged1 EC expression. CONCLUSIONS: Fzd7 expressed by EC drives postnatal angiogenesis via activation of Dvl/β-catenin signaling and can control the integrative interaction of Wnt and Notch signaling during postnatal angiogenesis

Transmission with Cardan Joint Parametre Influence to Centrifugal Pump Characteristics

Transmission with cardan joints and non­linear gearbox elements generates vibrations caused by spinning motion of transmission. This affects the pressure and productivity of centrifugal pump. The momentum of centrifugal pump in turn affects dynamic characteristics of transmission. In order to find the effect of transmission elements on centrifugal pump we investigate transmission composed of asynchronous electrical engine, gear box, cardan joint and Ziegler Ultra centrifugal pump. We create mathematical models of transmission and centrifugal pumps and investigate how the dynamic effects of transmission influence productivity centrifugal pump. This model can be applied to study the transmission parameters, effect of intake and outflow parameters on productivity of centrifugal pump and presence of cavitation. The paper includes results and conclusions of mathematical model. Santrauka Transmisija su kardanine jungtimi ir netiesiškumais pavarų dėžės elementuose generuoja transmisijos sukamojo judesio virpesius, kurie daro poveikį išcentrinio siurblio siurbliaračio sūkiams, generuojamam slėgiui ir jo našumui. Be to, siurbliaračio apkrovimo momentas veikia transmisijos dinamines charakteristikas. Norint nustatyti transmisijos elementų poveikį išcentrinio siurblio charakteristikoms, nagrinėjama transmisija, kuri sudaryta iš asinchroninio elektros variklio, pavarų dėžės, kardaninės jungties ir firmos „Ziegler Ultra Power“ išcentrinio siurblio. Sukurti transmisijos ir išcentrinio siurblio matematiniai modeliai, ištirta transmisijos dinaminio poveikio įtaka išcentrinio siurblio generuojamam našumui. Šiuo modeliu galima tirti transmisijos elementų parametrų, įsiurbimo ir išėjimo magistralių parametrų poveikį išcentrinio siurblio darbui, ir atvirkščiai, kavitacijos reiškinio atsiradimą išcentriniame siurblyje. Pateikti nagrinėjamos sistemos skaitinio modeliavimo rezultatai ir išvados. Reikšminiai žodžiai: asinchroninis elektros variklis; pavarų dėžė; kardaninė jungtis; išcentrinis siurblys

Sci signal

Endothelial cells serve as a barrier between blood and tissues. Maintenance of the endothelial cell barrier depends on the integrity of intercellular junctions, which is regulated by a polarity complex that includes the ζ isoform of atypical protein kinase C (PKCζ) and partitioning defective 3 (PAR3). We revealed that the E3 ubiquitin ligase PDZ domain-containing ring finger 3 (PDZRN3) regulated endothelial intercellular junction integrity. Endothelial cell-specific overexpression of Pdzrn3 led to early embryonic lethality with severe hemorrhaging and altered organization of endothelial intercellular junctions. Conversely, endothelial-specific loss of Pdzrn3 prevented vascular leakage in a mouse model of transient ischemic stroke, an effect that was mimicked by pharmacological inhibition of PKCζ. PDZRN3 regulated Wnt signaling and associated with a complex containing PAR3, PKCζ, and the multi-PDZ domain protein MUPP1 (Discs Lost-multi-PDZ domain protein 1) and targeted MUPP1 for proteasomal degradation in transfected cells. Transient ischemic stroke increased the ubiquitination of MUPP1, and deficiency of MUPP1 in endothelial cells was associated with decreased localization of PKCζ and PAR3 at intercellular junctions. In endothelial cells, Pdzrn3 overexpression increased permeability through a PKCζ-dependent pathway. In contrast, Pdzrn3 depletion enhanced PKCζ accumulation at cell-cell contacts and reinforced the cortical actin cytoskeleton under stress conditions. These findings reveal how PDZRN3 regulates vascular permeability through a PKCζ-containing complex

Human CD133+ progenitor cells promote the healing of diabetic ischemic ulcers by paracrine stimulation of angiogenesis and activation of Wnt signaling.

We evaluated the healing potential of human fetal aorta-derived CD133<sup>+</sup>progenitor cells and their conditioned medium (CD133<sup>+</sup> CCM) in a new model of ischemic diabetic ulcer. Streptozotocin-induced diabetic mice underwent bilateral limb ischemia and wounding. One wound was covered with collagen containing 2×10<sup>4</sup> CD133<sup>+</sup> or CD133<sup>−</sup> cells or vehicle. The contralateral wound, covered with only collagen, served as control. Fetal CD133<sup>+</sup> cells expressed high levels of wingless (Wnt) genes, which were downregulated following differentiation into CD133<sup>−</sup> cells along with upregulation of Wnt antagonists secreted frizzled-related protein (sFRP)-1, -3, and -4. CD133<sup>+</sup> cells accelerated wound closure as compared with CD133<sup>−</sup> or vehicle and promoted angiogenesis through stimulation of endothelial cell proliferation, migration, and survival by paracrine effects. CD133<sup>+</sup> cells secreted high levels of vascular endothelial growth factor (VEGF)-A and interleukin (IL)-8. Consistently, CD133<sup>+</sup> CCM accelerated wound closure and reparative angiogenesis, with this action abrogated by coadministering the Wnt antagonist sFRP-1 or neutralizing antibodies against VEGF-A or IL-8. In vitro, these effects were recapitulated following exposure of high-glucose-primed human umbilical vein endothelial cells to CD133<sup>+</sup> CCM, resulting in stimulation of migration, angiogenesis-like network formation and induction of Wnt expression. The promigratory and proangiogenic effect of CD133<sup>+</sup> CCM was blunted by sFRP-1, as well as antibodies against VEGF-A or IL-8. CD133<sup>+</sup> cells stimulate wound healing by paracrine mechanisms that activate Wnt signaling pathway in recipients. These preclinical findings open new perspectives for the cure of diabetic ulcers

Desert Hedgehog Promotes Ischemia-Induced Angiogenesis by Ensuring Peripheral Nerve Survival

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