Bim expression in endothelial cells and pericytes is essential for regression of the fetal ocular vasculature

Wang, Shoujian; Zaitoun, Ismail; Johnson, Ryan P.; Jamali, Nasim; Gurel, Zafer; Wintheiser, Catherine M; Strasser, Andreas; Lindner, Volkhard; Sheibani, Nader; Sorenson, Christine M.

doi:10.1371/journal.pone.0178198

Cited by 18 publications

(20 citation statements)

References 34 publications

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“…To validate specificity of Cre-mediated excision, we generated mice carrying a conditional Tomato allele and Pdgfrb-cre or Gfap-cre. We noted Tomato expression in retinal pericytes/vascular smooth muscle cells 40 , as we previously described for astrocytes (Fig. S3).…”

Section: Methodssupporting

confidence: 80%

Bcl-2 Expression in Pericytes and Astrocytes Impacts Vascular Development and Homeostasis

Zaitoun

Wintheiser

Jamali

et al. 2019

Sci Rep

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B-cell lymphoma 2 (Bcl-2) protein is the founding member of a group of proteins known to modulate apoptosis. Its discovery set the stage for identification of family members with either pro- or anti-apoptotic properties. Expression of Bcl-2 plays an important role during angiogenesis by influencing not only vascular cell survival, but also migration and adhesion. Although apoptosis and migration are postulated to have roles during vascular remodeling and regression, the contribution of Bcl-2 continues to emerge. We previously noted that the impaired retinal vascularization and an inability to undergo pathologic neovascularization observed in mice globally lacking Bcl-2 did not occur when mice lacked the expression of Bcl-2 only in endothelial cells. To further examine the effect of Bcl-2 expression during vascularization of the retina, we assessed its contribution in pericytes or astrocytes by generating mice with a conditional Bcl-2 allele (Bcl-2 Flox/Flox ) and Pdgfrb-cre (Bcl-2 PC mice) or Gfap-cre (Bcl-2 AC mice). Bcl-2 PC and Bcl-2 AC mice demonstrated increased retinal vascular cell apoptosis, reduced numbers of pericytes and endothelial cells and fewer arteries and veins in the retina. Bcl-2 PC mice also demonstrated delayed advancement of the superficial retinal vascular layer and aberrant vascularization of the deep vascular plexus and central retina. Although pathologic neovascularization in oxygen-induced ischemic retinopathy (OIR) was not affected by lack of expression of Bcl-2 in either pericytes or astrocytes, laser-induced choroidal neovascularization (CNV) was significantly reduced in Bcl-2 PC mice compared to littermate controls. Together these studies begin to reveal how cell autonomous modulation of apoptosis in vascular cells impacts development and homeostasis.

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Section: Methodssupporting

confidence: 80%

Bcl-2 Expression in Pericytes and Astrocytes Impacts Vascular Development and Homeostasis

Zaitoun

Wintheiser

Jamali

et al. 2019

Sci Rep

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“…When Bim was only deleted in endothelial cells or pericytes we observed attenuated retinal postnatal vascular remodeling, perhaps due to decreased rate of apoptosis. Although hyaloid vessel regression was attenuated in mice lacking Bim expression in endothelial cells or pericytes, they responded similar to their control littermates to oxygen-induced ischemic retinopathy [16]. Thus, a better understanding of the implications to angiogenesis associated with these changes are emerging.…”

Section: Plos Onementioning

confidence: 96%

“…The pro-apoptotic member Bim contains only one BH domain, BH3. Our laboratory has found Bim to be a central player modulating apoptosis of retinal endothelial cells and pericytes [16]. However, its role in modulating retinal astroglial cell apoptosis requires further delineation.…”

Section: Introductionmentioning

confidence: 98%

Bim expression modulates the pro-inflammatory phenotype of retinal astroglial cells

Falero-Perez

Sorenson

2020

PLoS ONE

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Apoptosis of neurovascular cells, including astroglial cells, contributes to the pathogenesis of diseases in which neurovascular disruption plays a central role. Bim is a pro-apoptotic protein that modulates not only apoptosis but also various cellular functions such as migration and extracellular matrix protein expression. Astroglial cells act as an intermediary between neural and vascular cells facilitating retinal vascular development and remodeling while maintaining normal vascular function and neuronal integrity. We previously showed that Bim deficient (Bim-/-) mice were protected from hyperoxia mediated vessel obliteration and ischemia-mediated retinal neovascularization. However, the underlying mechanisms and more specifically the role Bim expression in astroglial cells play remains elusive. Here, using retinal astroglial cells prepared from wild-type and Bim-/-mice, we determined the impact of Bim expression in retinal astroglial cell function. We showed that astroglial cells lacking Bim expression demonstrate increased VEGF expression and altered matricellular protein production including increased expression of thrombospondin-2 (TSP2), osteopontin and SPARC. Bim deficient astroglial cells also exhibited altered proliferation, migration, adhesion to various extracellular matrix proteins and increased expression of inflammatory mediators. Thus, our data emphasizes the importance of Bim expression in retinal astroglia cell autonomous regulatory mechanisms, which could influence neurovascular function.

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“…They are key factors contributing in endogenous vascular reparative processes and adaptation to hypoxia / ischemia-induced injury of cytotrophoblast [5]. Depending on their origin (activated or apoptotic fetal cells) exosomes appear to be distinguished in morphology, immune phenotypes, abilities to cargo some molecules (active proteins, pro-coagulants, growth factors, lipids, enzymes, micro-RNAs) and induce autocrine / paracrine effects on vasculature and trophoblast [6,7]. Apart from hypoxia /ischemia, insulin resistance, impaired fasting glucose, lipid toxicity and inflammation are recognized main regulators of cell secretom including exosomes [8].…”

Section: Abstract: Pregnancy; Preeclampsia; Exosomes; Vascular Complimentioning

confidence: 99%

Are Placental Cell-Derived Exosomes a Predictive Biomarker of Preeclampsia?

Berezin¹

2017

Med chem

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Placenta is endocrine organ that regulate biological function of several maternal tissues and fetal organs by specific mechanisms of cell-to-cell cooperation, which is realized via exosomes' secretion. Exosomes delivery some molecules, i.e., active proteins, pro-coagulants, growth factors, lipids, enzymes, micro-RNAs to target cells and induce autocrine / paracrine effects on vasculature and trophoblast. Interestingly, circulating number of exosomes derived from placenta cells in healthy pregnancies increases in 50-100 fold times to healthy volunteers and they may be detected in several biological fluids across all gestation age starting with 6 weeks of gestation. Moreover, pregnancies at risk of preeclampsia exhibit extremely increased levels of total exosomes and placental cell-derived-exosomes in blood when compared with woman at risk free of preeclampsia. Taking into consideration this fact, measure of circulating number of placental cell-derived-exosomes could be an individual probe for personification of a risk of life-threatening event across pregnancy. The short communication is depicted the role of placental cell-derived-exosomes as biomarker of preeclampsia in asymptomatic pregnancies.

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Bim expression in endothelial cells and pericytes is essential for regression of the fetal ocular vasculature

Cited by 18 publications

References 34 publications

Bcl-2 Expression in Pericytes and Astrocytes Impacts Vascular Development and Homeostasis

Bcl-2 Expression in Pericytes and Astrocytes Impacts Vascular Development and Homeostasis

Bim expression modulates the pro-inflammatory phenotype of retinal astroglial cells

Are Placental Cell-Derived Exosomes a Predictive Biomarker of Preeclampsia?

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