Loss of Id3 (Inhibitor of Differentiation 3) Increases the Number of IgM-Producing B-1b Cells in Ischemic Skeletal Muscle Impairing Blood Flow Recovery During Hindlimb Ischemia.
Loss of Id3 (Inhibitor of Differentiation 3) Increases the Number of IgM-Producing B-1b Cells in Ischemic Skeletal Muscle Impairing Blood Flow Recovery During Hindlimb Ischemia.
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DOI：
10.1161/atvbaha.120.315501
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发表时间：
2022-01
期刊：
影响因子：
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通讯作者：
McNamara CA
中科院分区：
文献类型：
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作者：
Osinski V;Srikakulapu P;Haider YM;Marshall MA;Ganta VC;Annex BH;McNamara CA
在外周动脉疾病(PAD)时肢体缺血的情况下，新生血管可以维持甚至改善组织的灌注度。调节这一过程的分子和细胞机制还不完全清楚。我们研究了分化抑制因子3(ID3)在小鼠后肢缺血模型中调节血流的潜在作用(S)。通过股动脉结扎和切除建立HLI模型，激光多普勒血流成像定量检测血流恢复情况。在HLI第14天和第21天，ID3整体缺失的小鼠的血流灌注恢复明显受损。血管内皮细胞或髓系细胞特异性缺失ID3对血流恢复无影响，而B细胞特异性敲除ID3(Id3BKO)则显示血流恢复显著减弱。流式细胞仪检测显示缺血诱导的T细胞和髓系细胞数在HLI后7d无明显差异，但Id3BKO组B-1b细胞显著增加。与这些发现一致的是，酶联免疫吸附试验显示骨骼肌和血浆免疫球蛋白M增加。体外实验显示，Id3BKO小鼠胫骨前肌内皮细胞用产生α的B-1b细胞的条件培养液处理后，细胞增殖减少，细胞死亡增加，总CD31+和CD31+SMA+血管密度降低。这项研究首次证明了B细胞特异性ID3在HLI期间维持血流恢复中的作用。结果表明，ID3在HLI期间促进血流和限制表达IgM的B-1b细胞的增殖中起作用。这些发现为研究PAD的发病机制提供了新的机制。
Neovascularization can maintain and even improve tissue perfusion in the setting of limb ischemia during peripheral artery disease (PAD). The molecular and cellular mechanisms mediating this process are incompletely understood. We investigate the potential role(s) for Inhibitor of differentiation 3 (Id3) in regulating blood flow in a murine model of hind limb ischemia (HLI). HLI was modeled through femoral artery ligation and resection and blood flow recovery was quantified by Laser Doppler perfusion imaging. Mice with global Id3 deletion had significantly impaired perfusion recovery at 14 and 21 days of HLI. Endothelial- or myeloid cell-specific deletion of Id3 revealed no effect on perfusion recovery while B cell-specific knockout of Id3 (Id3BKO) revealed a significant attenuation of perfusion recovery. Flow cytometry revealed no differences in ischemia-induced T cells or myeloid cell numbers at 7 days of HLI, yet there was a significant increase in B-1b cells in Id3BKO. Consistent with these findings, ELISA demonstrated increases in skeletal muscle and plasma IgM. In vitro experiments demonstrated reduced proliferation and increased cell death when ECs were treated with conditioned media from IgM-producing B-1b cells and tibialis anterior muscles in Id3BKO mice showed reduced density of total CD31+ and αSMA+CD31+ vessels. This study is the first to demonstrate a role for B cell-specific Id3 in maintaining blood flow recovery during HLI. Results suggest a role for Id3 in promoting blood flow during HLI and limiting IgM-expressing B-1b cell expansion. These findings present new mechanisms to investigate in PAD pathogenesis.