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Abstract
Inflammaging is defined as low-grade, chronic, systemic inflammation in aging, in the absence of overt infection. Age-associated deterioration of gastrointestinal function could be ascribed to the inflammaging, although evidence is yet to emerge. Here we show that microvessels in aging mouse intestine were progressively deprived of supportive structures, microvessel-associated pericytes and adherens junction protein vascular endothelial (VE)-cadherin, and became leaky. This alteration was ascribed to up-regulation of angiopoetin-2 in microvascular endothelial cells. Up-regulation of the angiopoietin-2 was by TNF-α, originated from M2-like residential CD206+ macrophages, proportion of which increases as animal ages. It was concluded that antigenic burdens encountered in intestine throughout life create the condition of chronic stage of inflammation, which accumulates M2-like macrophages expressing TNF-α. The TNF-α induces vascular leakage to facilitate recruitment of immune cells into intestine under the chronic inflammatory setting.
Highlights
Aging is a dynamic process of life-long adaptation of the animal to ever changing internal and external environments, resulting in body function decline
This was further verified by another pericyte marker PDFGR-β12 which appeared to be virtually depleted in old mice as well (Supplementary Fig. 1)
Since angiopoietin 2 (ANG2) binding to TIE-2 triggers degradation of the vascular endothelial (VE)-cadherin, we examined the expression of VE-Cadherin in CD31+ EC in lamina propria (LP) after IF staining and observed age-dependent loss (Fig. 1C)
Summary
Aging is a dynamic process of life-long adaptation of the animal to ever changing internal and external environments, resulting in body function decline. An hallmark of age-associated chronic inflammation would be macrophage infiltration[2]. Age-associated deterioration of gastrointestinal function[6,7] could be ascribed to the inflammaging, substantial evidence is yet to emerge. ANG1 signaling is critical in the stabilization and maturation of vessels by recruiting mural cells, while ANG2 antagonizes the effect of ANG1–mediated stimulation of TIE-2 under the condition of chronic inflammation leading to vessel destabilization and pericyte dropout. TIE-2 signaling mediated by ANG1/2 is known to be involved in controlling endothelial cell[9] permeability[8]. The ANG2 binding to TIE-2 triggers degradation of an adherens junction protein vascular endothelial (VE)-cadherin in the junctional complexes via non-receptor Tyr kinase Src, thereby increasing EC permeability. Age-associated deterioration of gastrointestinal function could be ascribed to the increased EC permeability
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