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Abstract 508: Prolonged Thrombus Resolution Leading to Abnormal Collagen Fibrillogenesis and Angiogenesis in Injured Arteries of Type III Collagen-Deficient Mice: a Paradoxical Mechanism for ‘Tissue Fragility’ in Vascular Ehlers-Danlos Syndrome and Spontaneous Cervical Artery Dissection

血栓 医学 病理 伤口愈合 血管生成 血栓形成 纤维帽 心脏病学 内科学 外科
作者
Amy J. Reid,Yuqiang Bai,Lorenzo F. Perez,Naomi Ogawa,L. Maximilian Buja,Alvin T. Yeh,Dianna M. Milewicz
出处
期刊:Arteriosclerosis, Thrombosis, and Vascular Biology [Lippincott Williams & Wilkins]
卷期号:33 (suppl_1)
标识
DOI:10.1161/atvb.33.suppl_1.a508
摘要

Patients with COL3A1 mutations that impede secretion of type III collagen into matrix develop wounds that heal poorly following cutaneous injury. They are also predisposed to vascular complications like catastrophic rupture or dissection of cervical arteries and stroke. We sought to determine if low production of type III collagen would also interrupt arterial thrombus resolution, a process resembling wound healing, and whether defects contribute to risk of dissection. We injured cervical elastic arteries in mice by ligation of the left common carotid, halting proximal blood flow. Strikingly, injured arteries from Col3a1 +/- mice develop thrombi over three weeks that resist resolution more often than those in wild-type littermates ( p =.002). The unresolved thrombi in Col3a1 +/- arteries also retain a higher burden of macrophages ( p =.043) and proliferative α-actin-positive cells ( p =.034), while mutant arteries display vascular channels within the media ( p =.015) that are partially lined with endothelial cells, consistent with residual neoangiogenesis. At two weeks, burdens of macrophages ( p =.009), proliferative cells ( p =.028), and vascular channels ( p =.019) are also higher in Col3a1 +/- arteries, despite actively resolving thrombi of equal length between the two groups ( p =.338), suggesting that neoangiogenesis results specifically from lower Col3a1 dose. Treating injured mice with rapamycin halts thrombus resolution in the early inflammatory phase of both genotypes and normalizes the incidence of vascular channels in Col3a1 +/- arteries at three weeks ( p =1.00), suggesting that vascular channels result secondary to thrombus resolution and not from structural weakness in type III collagen deficient arteries. Patient-derived COL3A1 mutant myofibroblasts in 3D culture models of fibrin remodeling accumulate less extracellular type I collagen following TGFβ1 stimulation but persistently upregulate expression of Acta2 , relative to control cells whose Acta2 expression levels peak and subside as collagen accumulates by seven days. These data implicate dysregulated thrombus remodeling in response to injury that increases the risk for medial neoangiogenesis, which may also increase the risk for dissection in affected arteries after injury.

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