The impact of chronic mild hypoxia on cerebrovascular remodelling; uncoupling of angiogenesis and vascular breakdown.
The impact of chronic mild hypoxia on cerebrovascular remodelling; uncoupling of angiogenesis and vascular breakdown.
复制标题
DOI：
10.1186/s12987-021-00284-x
复制
发表时间：
2021-11-17
影响因子：
7.3
通讯作者：
Milner R
中科院分区：
文献类型：
--
作者：
Halder SK;Milner R
慢性轻度缺氧（CMH, 8% O2）刺激大脑中强健的血管重构，但也会引发短暂的血管破坏。这就提出了一个基本问题：血管泄漏是血管生成重塑的不良副作用，还是一种与内皮细胞增殖无关的病理反应，其中氧水平下降引发内皮细胞功能障碍？为了回答这个问题，将小鼠暴露在CMH （8% O2）中长达14天，之后，通过免疫荧光（IF）检查脑组织，以确定哪种类型的血管（小动脉、毛细血管或小静脉）与内皮细胞增殖和血管泄漏最常见，以及这与紧密连接蛋白表达的关系。采用DiI检测血管灌注。数据分析采用单因素方差分析（ANOVA），随后采用Tukey多重比较事后检验。观察到以下情况：(1)大多数内皮细胞增殖和血管外纤维蛋白原泄漏发生在毛细血管中，在较小程度上发生在小静脉中；(2)令我们惊讶的是，内皮细胞增殖和血管外纤维蛋白原泄漏从未共定位；(3)然而有趣的是，内皮细胞增殖与血管内纤维蛋白原染色模式密切相关，而在稳定的血管中没有见过；(4)DiI灌注研究显示血管生成血管充分灌注。(5)溴脱氧尿苷（BrdU）标记作为一种更永久地标记增殖内皮细胞的手段，证实内皮细胞增殖与血管外纤维蛋白原泄漏之间缺乏任何联系，而(6)相反，在血管外泄漏中检测到增殖性小胶质细胞。综上所述，我们的研究结果支持这样一种观点，即在短期内，缺氧诱导的内皮细胞增殖会触发短暂的纤维蛋白原沉积在血管生成血管的壁上，但这些血管不会发生明显的血管泄漏。重要的是，内皮细胞增殖和血管外纤维蛋白原泄漏从未共定位，这表明血管外泄漏不是血管生成内皮细胞增殖的不良副作用，而是一种对缺氧的功能失调的血管反应，发生在一组不同的非血管生成血管中。
Chronic mild hypoxia (CMH, 8% O2) stimulates robust vascular remodelling in the brain, but it also triggers transient vascular disruption. This raises the fundamental question: is the vascular leak an unwanted side-effect of angiogenic remodelling or is it a pathological response, unrelated to endothelial proliferation, in which declining oxygen levels trigger endothelial dysfunction? To answer this question, mice were exposed to CMH (8% O2) for periods up to 14 days, after which, brain tissue was examined by immunofluorescence (IF) to determine which type of blood vessel (arteriole, capillary or venule) was most commonly associated with endothelial proliferation and vascular leak and how this correlated with tight junction protein expression. Vascular perfusion was examined using DiI. Data were analysed using one-way analysis of variance (ANOVA) followed by Tukey’s multiple comparison post-hoc test. The following was observed: (1) most endothelial proliferation and extravascular fibrinogen leak occurred in capillaries and to a lesser degree in venules, (2) much to our surprise, endothelial proliferation and extravascular fibrinogen leak never colocalized, (3) interestingly however, endothelial proliferation was strongly associated with an intravascular fibrinogen staining pattern not seen in stable blood vessels, (4) DiI perfusion studies revealed that angiogenic vessels were adequately perfused, suggesting that fibrinogen retention in angiogenic vessels is not due to temporary closure of the vessel, but more likely because fibrinogen is retained within the vessel wall, (5) bromodeoxyuridine (BrdU) labelling as a means to more permanently label proliferating endothelial cells, confirmed lack of any connection between endothelial proliferation and extravascular fibrinogen leak, while (6) in contrast, proliferating microglia were detected within extravascular leaks. Taken together, our findings support the concept that in the short-term, hypoxia-induced endothelial proliferation triggers transient fibrinogen deposition within the walls of angiogenic blood vessels, but no overt vascular leak occurs in these vessels. Importantly, endothelial proliferation and extravascular fibrinogen leaks never co-localize, demonstrating that extravascular leak is not an unwanted side-effect of angiogenic endothelial proliferation, but rather a dysfunctional vascular response to hypoxia that occurs in a distinct group of non-angiogenic blood vessels.
登录
查看更多内容
影响因子：
3.3
作者：
Kuo, NT;Benhayon, D;LaManna, JC
通讯作者：
LaManna, JC
DOI：
10.1016/s0169-328x(99)00261-2
发表时间：
1999-12-10
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Pichiule, P;Chávez, JC;LaManna, JC
通讯作者：
LaManna, JC
影响因子：
3.5
作者：
Milner, Richard;Hung, Stephanie;del Zoppo, Gregory J.
通讯作者：
del Zoppo, Gregory J.
影响因子：
3.3
作者：
LAMANNA, JC;VENDEL, LM;FARRELL, RM
通讯作者：
FARRELL, RM
影响因子：
5.3
作者：
Li, Longxuan;Liu, Fudong;Welser-Alves, Jennifer V.;McCullough, Louise D.;Milner, Richard
通讯作者：
Milner, Richard