Seattle Institute for Biomedical and Clinical Research, Seattle, WA, USA.
VA Puget Sound Health Care System, Seattle, WA, USA.
Angiogenesis. 2023 Feb;26(1):63-76. doi: 10.1007/s10456-022-09851-8. Epub 2022 Aug 10.
Progression of atherosclerosis is associated with a maladaptive form of angiogenesis which contributes to intraplaque hemorrhage and plaque disruption. Hypoxia has been implicated in mechanisms of angiogenic neovessel fragility and atherosclerotic plaque destabilization. We used ex vivo and in vivo models to characterize the effect of oxygen (O) on the formation, stability and tendency to bleed of human plaque-induced neovessels. Plaque explants potently stimulated the ex vivo angiogenic response of rat aortic rings at atmospheric O levels. Severe hypoxia (1% O) inhibited plaque-induced angiogenesis and pericyte recruitment causing neovessel breakdown, whereas increasing O levels dose dependently enhanced pericyte numbers and neovessel stability. Plaque fragments implanted subcutaneously with or without aortic rings in SCID mice stimulated the host angiogenic response with plaques causing minimal or no hemorrhages and plaques co-implanted with aortic rings causing marked hemorrhages. Plaque/aortic ring-induced hemorrhages were reduced in mice exposed to moderate hyperoxia (50% O). Hyperoxia downregulated expression of the hypoxia-sensitive genes Ca9, Ca12 and VegfA and increased influx into implants of mesenchymal cells reactive for the pericyte marker NG2. In both ex vivo and in vivo models, O promoted expression of vasostabilizing genes required for pericyte recruitment (Angpt1, Pdgfb), basement membrane assembly (Col4A1), and tight junction formation (Cldn5 and/or Ocln). Our results suggest that formation of neovessels that are stable, pericyte-coated, and resistant to bleeding requires adequate tissue oxygenation. Understanding the mechanisms by which O stabilizes neovessels and mitigates neovessel bleeding may lead to new therapies for the prevention of atherosclerosis complications.
动脉粥样硬化的进展与一种适应性不良的血管生成形式有关，这种形式导致斑块内出血和斑块破裂。缺氧被认为与血管生成新血管的脆弱性和动脉粥样硬化斑块的不稳定性机制有关。我们使用离体和体内模型来描述氧（O）对人斑块诱导的新血管形成、稳定性和出血倾向的影响。斑块外植体在大气 O 水平下强烈刺激大鼠主动脉环的离体血管生成反应。严重缺氧（1%O）抑制斑块诱导的血管生成和周细胞募集，导致新血管破裂，而增加 O 水平则依赖于剂量增加周细胞数量和新血管的稳定性。斑块碎片皮下植入，无论是否有主动脉环，在 SCID 小鼠中刺激宿主血管生成反应，斑块引起最小或无出血，而斑块与主动脉环共同植入则引起明显出血。暴露于中等高氧（50%O）的小鼠中，斑块/主动脉环诱导的出血减少。高氧下调缺氧敏感基因 Ca9、Ca12 和 VegfA 的表达，并增加骨髓细胞流入植入物的反应性，这些细胞对周细胞标志物 NG2 呈阳性。在离体和体内模型中，O 促进了招募周细胞所需的血管稳定基因的表达（Angpt1、Pdgfb）、基底膜组装（Col4A1）和紧密连接形成（Cldn5 和/或 Ocln）。我们的结果表明，形成稳定、被周细胞覆盖且不易出血的新血管需要足够的组织氧合。了解 O 稳定新血管和减轻新血管出血的机制可能会导致预防动脉粥样硬化并发症的新疗法。
