Heidari Zahra, Naeimzadeh Yasaman, Fallahi Jafar, Savardashtaki Amir, Razban Vahid, Khajeh Sahar
Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.
Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.
Curr Mol Med. 2024;24(9):1135-1151. doi: 10.2174/0115665240258746230919165935.
Tissue factor (TF) is an integral transmembrane protein associated with the extrinsic coagulation pathway. TF gene expression is regulated in response to inflammatory cytokines, bacterial lipopolysaccharides, and mechanical injuries. TF activity may be affected by phosphorylation of its cytoplasmic domain and alternative splicing. TF acts as the primary initiator of physiological hemostasis, which prevents local bleeding at the injury site. However, aberrant expression of TF, accompanied by the severity of diseases and infections under various pathological conditions, triggers multiple signaling pathways that support thrombosis, angiogenesis, inflammation, and metastasis. Protease-activated receptors (PARs) are central in the downstream signaling pathways of TF. In this study, we have reviewed the TF signaling pathways in different pathological conditions, such as wound injury, asthma, cardiovascular diseases (CVDs), viral infections, cancer and pathological angiogenesis. Angiogenic activities of TF are critical in the repair of wound injuries and aggressive behavior of tumors, which are mainly performed by the actions of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 (HIF1-α). Pro-inflammatory effects of TF have been reported in asthma, CVDs and viral infections, including COVID-19, which result in tissue hypertrophy, inflammation, and thrombosis. TF-FVII induces angiogenesis via clotting-dependent and -independent mechanisms. Clottingdependent angiogenesis is induced via the generation of thrombin and cross-linked fibrin network, which facilitate vessel infiltration and also act as a reservoir for endothelial cells (ECs) growth factors. Expression of TF in tumor cells and ECs triggers clotting-independent angiogenesis through induction of VEGF, urokinase-type plasminogen activator (uPAR), early growth response 1 (EGR1), IL8, and cysteine-rich angiogenic inducer 61 (Cyr61).
组织因子（TF）是一种与外源性凝血途径相关的整合跨膜蛋白。TF基因表达受炎症细胞因子、细菌脂多糖和机械损伤的影响而被调控。TF的活性可能受其胞质结构域磷酸化和可变剪接的影响。TF作为生理性止血的主要启动因子，可防止损伤部位局部出血。然而，在各种病理条件下，TF的异常表达伴随着疾病和感染的严重程度，会触发支持血栓形成、血管生成、炎症和转移的多种信号通路。蛋白酶激活受体（PARs）在TF的下游信号通路中起核心作用。在本研究中，我们综述了不同病理条件下的TF信号通路，如伤口损伤、哮喘、心血管疾病（CVDs）、病毒感染、癌症和病理性血管生成。TF的血管生成活性在伤口损伤修复和肿瘤侵袭行为中至关重要，主要由血管内皮生长因子（VEGF）和缺氧诱导因子-1（HIF1-α）的作用介导。TF在哮喘、CVDs和病毒感染（包括COVID-19）中的促炎作用已被报道，这些作用会导致组织肥大、炎症和血栓形成。TF-FVII通过凝血依赖性和非依赖性机制诱导血管生成。凝血依赖性血管生成是通过凝血酶的产生和交联纤维蛋白网络诱导的，这有助于血管浸润，并作为内皮细胞（ECs）生长因子的储存库。肿瘤细胞和ECs中TF的表达通过诱导VEGF、尿激酶型纤溶酶原激活剂（uPAR）、早期生长反应1（EGR1）、IL8和富含半胱氨酸的血管生成诱导因子61（Cyr61）触发非凝血依赖性血管生成。
