Systemic influences contribute to prolonged microvascular rarefaction after brain irradiation: a role for endothelial progenitor cells

Abstract

Whole brain radiation therapy (WBRT) induces profound cerebral microvascular rarefaction throughout the hippocampus. Despite the vascular loss and localized cerebral hypoxia, angiogenesis fails to occur, which subsequently induces long-term deficits in learning and memory. The mechanisms underlying the absence of vessel recovery after WBRT are unknown. We tested the hypotheses that vascular recovery fails to occur under control conditions as a result of loss of angiogenic drive in the circulation, chronic tissue inflammation, and/or impaired endothelial cell production/recruitment. We also tested whether systemic hypoxia, which is known to promote vascular recovery, reverses these chronic changes in inflammation and endothelial cell production/recruitment. Ten-week-old C57BL/6 mice were subjected to a clinical series of fractionated WBRT: 4.5-Gy fractions 2 times/wk for 4 wk. Plasma from radiated mice increased in vitro endothelial cell proliferation and adhesion compared with plasma from control mice, indicating that WBRT did not suppress the proangiogenic drive. Analysis of cytokine levels within the hippocampus revealed that IL-10 and IL-12(p40) were significantly increased 1 mo after WBRT; however, systemic hypoxia did not reduce these inflammatory markers. Enumeration of endothelial progenitor cells (EPCs) in the bone marrow and circulation indicated that WBRT reduced EPC production, which was restored with systemic hypoxia. Furthermore, using a bone marrow transplantation model, we determined that bone marrow-derived endothelial-like cells home to the hippocampus after systemic hypoxia. Thus, the loss of production and homing of EPCs have an important role in the prolonged vascular rarefaction after WBRT.

Role of NADPH oxidase in radiation-induced pro-oxidative and pro-inflammatory pathways in mouse brain

“…Briefly, 10-week-old mice were anesthetized with ketamine-xylazine (intraperitoneal injection, 100–15 mg/kg) and received a clinical fractionated dose of whole brain irradiation using a 137 Cs γ irradiator (Gammacell® 40; Best Threratronics, Ottawa, Ontario, Canada) with a Cerrobend shield to collimate the beam only to whole mouse brain and minimize its exposure to other parts of body. In addition, the radiation dose received by the head of mice was verified using radiochromic film dosimetry, as previously described (Ashpole et al, 2014). Six dosimetry film positions were used to measure representations of the anterior and posterior surfaces as well as the centers of the head and body of the mice.…”

Mechanisms of Vascular Aging

“…In that regard it is interesting that known interventions that cause extensive DNA damage (e.g. whole brain irradiation) result in significant phenotypic and functional alterations in endothelial cells, promoting microvascular rarefaction, impaired vasodilation and pro-inflammatory changes, mimicking several aspects of the aging phenotype 84, 116, 117 . In vascular endothelial cells DNA damage readily triggers replicative senescence (see below) 84 , to prevent propagation of damaged DNA.…”

Pharmacological or genetic depletion of senescent astrocytes prevents whole brain irradiation–induced impairment of neurovascular coupling responses protecting cognitive function in mice

“…In the past decade, a new concept has emerged, suggesting that WBIinduced cognitive decline is a clinically relevant case of accelerated cerebrovascular aging. Importantly, there is strong preclinical evidence that, similar to aging, the profound harmful effects of WBI on cognitive function are due, at least in part, to dysregulated CBF (Ungvari et al 2017;Ashpole et al 2014;Warrington et al 2013).…”