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

Abstract

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.

Pericytes Across the Lifetime in the Central Nervous System

“…Evidence of these age-related neurovascular changes in humans is particularly striking, especially when considering that this may be occurring in normal aging. Finally, a notable study showed that even aside from BBB leakiness, there is an age-related shift in transcytosis at the BBB, involving a decrease in receptor-mediated transport, which can heavily influence brain homeostasis (Yang et al, 2020). This study also suggested that this age-related change in transcytosis may be influenced by pericyte loss (Yang et al, 2020).…”

“…Finally, a notable study showed that even aside from BBB leakiness, there is an age-related shift in transcytosis at the BBB, involving a decrease in receptor-mediated transport, which can heavily influence brain homeostasis (Yang et al, 2020). This study also suggested that this age-related change in transcytosis may be influenced by pericyte loss (Yang et al, 2020). Needless to say, the impacts of aging on the BBB are likely to be due to changes in its components.…”

7, 8-Dihydroxyflavone, a TrkB receptor agonist, provides minimal protection against retinal vascular damage during oxygen-induced ischemic retinopathy

“…Preparation of wholemount retina for assessing vessel obliteration and neovascularization at different time points was done as we described previously [ 30 – 32 ]. Briefly, the collected eyeballs were fixed (2–3 hours) in 4% paraformaldehyde then washed in PBS (3 times) before placed in methanol and kept at -20°C until used.…”

Hypoxic–ischemic injury causes functional and structural neurovascular degeneration in the juvenile mouse retina

“…Immunofluorescence staining of retinal wholemounts was performed as we previously described with little modification 54 , 61 . Eyes were enucleated immediately post-mortem following euthanasia and fixed in 4% PFA for 10 min at room temperature, washed three times in PBS, and then transferred to methanol and kept at − 20 °C until stained.…”