Co-regulation of developmental vascular anomalies by fibronectin and collagen

纤连蛋白和胶原蛋白共同调节发育性血管异常

• 批准号: 9921446
• 负责人: Angela J Glading
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2021-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9921446
• 关键词: Adhesions; Adult; Affect; Age; Animals; Area; Basement membrane; Binding; Biology; Biomedical Research; Blood Vessels; CCM1 gene; Cardiovascular Diseases; Cavernous Hemangioma; Cell Communication; Cell Culture Techniques; Cell Line; Cells; Cerebrum; Child; Collagen; DNA Sequence Alteration; Data; Deposition; Development; Diagnosis; Disease; Endothelial Cells; Endothelium; Environment; Exhibits; Exploratory/Developmental Grant; Extracellular Matrix; Extracellular Matrix Proteins; Extracellular Protein; Family; Fibronectins; Genetic; Growth; Hemangioma; Implant; In Vitro; Integrin Binding; Integrin alphaVbeta3; Integrins; Intercellular Junctions; Knowledge; Laminin; Lesion; Life; Link; Longevity; Measures; Mediating; Modeling; Mus; Pathogenesis; Pathologic; Pathology; Patients; Peptides; Phenotype; Population; Positioning Attribute; Process; Proteins; Quality of life; Regulation; Role; Signal Transduction; Smooth Muscle Myocytes; Strawberry nevus; Structure; Structure-Activity Relationship; Testing; Therapeutic Agents; Tube; Tumor Angiogenesis; Tumor Biology; Vascular Endothelial Growth Factors; angiogenesis; base; cerebral cavernous malformations; cerebrovascular; developmental disease; in vivo; inhibitor/antagonist; malformation; mouse model; novel; prevent; scaffold; subcutaneous; support network; treatment strategy; wound healing

Project Summary The term vascular anomaly encompasses a broad spectrum of diseases, including the extremely common vasoproliferative disorder infantile hemangioma, and more rare pathologies such as cerebral cavernous malformation. Together, these diseases are estimated to affect more than 10% of the world’s population, and most often occur in children under the age of 5. Several forms of vascular anomalies exhibit an increase in expression of the extracellular matrix protein fibronectin, despite their cause being traced to disparate genetic mutations. Normal adult vascular basement membrane is comprised mainly of laminin and collagen and lacks fibronectin. Thus, the presence of fibronectin in infantile hemangioma, cavernous angioma/cerebral cavernous malformation, Sturge-Weber associated hemangioma, and VHL-disease associated hemangioma, among others, could contribute to a heretofore unidentified pathological mechanism. Fibronectin can stimulate endothelial proliferation and neo-angiogenesis in vitro, however, the role of fibronectin in the pathogenesis of vascular malformations has not been directly determined. Of the many cellular interactions mediated by fibronectin, its interaction with collagen is one of the least understood. Fibronectin and collagen appear to act synergistically to promote angiogenesis, and our new preliminary data show that blocking this interaction inhibits angiogenic tube formation. As the interaction between fibronectin and collagen has not been studied in an endothelial context, several fundamental questions remain about the role of this interaction in normal endothelial cells and in the development of vascular anomalies. Thus, we hypothesize that the fibronectin/collagen interaction regulates neo-angiogenesis and contributes to the formation of vascular anomalies. In this proposal, we will determine the contribution of fibronectin/collagen binding to matrix deposition and stability in endothelial cell cultures, and how this interaction regulates the formation of new vessels in vitro and in vivo by examining whether a peptide inhibitor of this interaction, R1R2, reduces the presence of collagen in the matrix, increases collagen internalization, and inhibits tube formation in vitro and new vessel growth in vivo. In addition, we will determine whether fibronectin/collagen binding contributes to the abnormal vessel formation in mouse models of cerebral cavernous malformation and hemangioma. Together, these data will determine the role of the fibronectin/collagen interaction in normal angiogenesis and the development of vascular anomalies, provide proof-of-principle that a common mechanism underlies the pathogenesis of vascular anomalies, and support further studies of R1R2 as a therapeutic agent.

项目概要 血管异常一词涵盖了广泛的疾病，包括极其常见的疾病 血管增殖性疾病婴儿血管瘤，以及更罕见的病变，例如脑海绵状血管瘤 畸形。据估计，这些疾病总共影响了世界 10% 以上的人口，并且 最常发生在 5 岁以下的儿童中。几种形式的血管异常表现出血管异常的增加 细胞外基质蛋白纤连蛋白的表达，尽管其原因可追溯到不同的遗传因素 突变。正常成人血管基底膜主要由层粘连蛋白和胶原蛋白组成，缺乏 纤连蛋白。因此，婴儿血管瘤、海绵状血管瘤/脑海绵状血管瘤中存在纤连蛋白 畸形、Sturge-Weber 相关血管瘤和 VHL 疾病相关血管瘤等 其他的，可能有助于迄今为止尚未确定的病理机制。纤连蛋白可以刺激 体外内皮增殖和新血管生成，然而，纤连蛋白在发病机制中的作用 血管畸形尚未直接确定。在许多细胞介导的相互作用中 纤连蛋白与胶原蛋白的相互作用是人们最不了解的相互作用之一。纤连蛋白和胶原蛋白似乎起作用 协同促进血管生成，我们新的初步数据表明，阻断这种相互作用 抑制血管生成管的形成。由于纤连蛋白和胶原蛋白之间的相互作用尚未被研究 在内皮环境中，关于这种相互作用在正常情况下的作用仍然存在一些基本问题 内皮细胞和血管异常的发展。因此，我们假设 纤连蛋白/胶原蛋白相互作用调节新血管生成并有助于血管的形成 异常。在本提案中，我们将确定纤连蛋白/胶原蛋白与基质结合的贡献 内皮细胞培养物中的沉积和稳定性，以及这种相互作用如何调节新细胞的形成 通过检查这种相互作用的肽抑制剂 R1R2 是否会降低血管的体外和体内 基质中存在胶原蛋白，增加胶原蛋白内化，并抑制体外管形成 体内新血管的生长。此外，我们将确定纤连蛋白/胶原蛋白结合是否有助于 脑海绵状血管瘤和血管瘤小鼠模型中的异常血管形成。一起， 这些数据将确定纤连蛋白/胶原蛋白相互作用在正常血管生成中的作用以及 血管异常的发展，提供原理证明，证明血管异常的共同机制 血管异常的发病机制，并支持 R1R2 作为治疗剂的进一步研究。