ABNORMAL VASCULAR CELL INTERACTIONS IN BRAIN AVMs

该计划的项目2所代表的一组研究建立在临床科学家和基础科学家之间的合作基础上。我们将描述脑动静脉畸形(BAVM)相关的血管生物学现象。该项目的优势是并行的机械性调查加上大量的新病例登记，从而允许临床数据与生物组织分析数据的关联。这种联系是独特和重要的，因为脑动静脉畸形代表了广泛的生理变化。将研究三种主要类型的组织：(1)脑动静脉畸形结节(n=80)，异常扩张的血管形成直接的高流量动静脉分流，没有介入的毛细血管床；(2)邻近结构正常的脑(n=40)；(3)癫痫手术的对照脑(n=40)。两者都有 将使用人体外科标本和细胞培养系统。我们的假设如下：(1)BAVM代表(A)内皮细胞(EC)有丝分裂原、血管内皮生长因子(VEGF)相对增加，而(B)Tie-2/Ang(血管生成素)途径招募和维持内皮周围支持结构(例如，平滑肌细胞和 周细胞)。这种不平衡最初会导致微分流形成(流量增加)。当血管内皮生长因子受体(VEGF-R)激活时，Ang-2信号的增加有利于BAVM的生长。脑动静脉畸形的生长和消退需要细胞外基质的调节。(2)基质金属蛋白酶(MMPs)降解BAVM血管中的细胞外基质。细胞外基质的过度降解会使脑动静脉畸形血管破裂(=颅内出血)。(3)机械上，超生理水平的Ang-2作为反馈机制的一部分或通过阻断Ang-1对Tie-2的刺激，下调BAVM中Tie-2的表达，而Ang-1不被Ang-1对抗。意义：阐明BAVM中异常血管生成的途径有助于识别临床相关的生物学现象，其机制可在细胞培养和动物模型中进一步研究。生物学数据与临床数据的相关性可能有助于预测脑动静脉畸形的临床行为，并有助于临床管理的风险分层。

The set of studies represented by Project 2 of the Program builds on the collaboration between the clinical and the basic scientists. We will characterize the vascular biological phenomena associated with brain arteriovenous malformations (BAVMs). The Strength of this project is the parallel mechanistic investigations coupled with a large new case enrollment, thus allowing correlation of clinical data with biological tissue assay data. This linkage is unique and important because BAVMs represent a broad spectrum of physiological alterations. Three primary types of tissue will be studied: (1) BAVM nidus (n=80), a tangle of abnormally dilated vessels forming a direct high flow arteriovenous shunt without an intervening capillary bed; (2) adjacent structurally-normal brain (n=40); and (3) control brain from epilepsy surgery (n=40). Both human surgical specimens and cell culture systems will be utilized. Our hypotheses are the following: (1) BAVMs represent a relative increase in (a) endothelial cell (EC) mitogens, vascular endothelial growth factor (VEGF), compared to (b) the Tie-2 / angiopoietin (Ang) pathway that recruits and maintains periendothelial support structures (e.g., smooth muscle cells and pericytes). This imbalance initially leads to micro-shunt formation (increased flow). BAVM growth is favored by increased Ang-2 signaling when VEGF receptor (VEGF-R) activation is ongoing. BAVM growth and regression will require modulation of extracellular matrix. (2) Matrix metalloproteinases (MMPs) degrade the extracellular matrix in the BAVM vessels. Excessive degradation of the extracellular matrix will predispose the BAVM vessel to rupture (= intracranial hemorrhage). (3) Mechanistically, supra-physiological levels of Ang-2, unopposed by Ang-1, down-regulates Tie-2 expression in BAVMs as part of a feedback mechanism or by blocking Ang-1 stimulation on Tie-2. Significance: Elucidating the pathways involved in abnormal angiogenesis in BAVMs can facilitate identification of clinically relevant biological phenomena whose mechanisms can be further studied in cell culture and animal models. Correlation of biological data with clinical data may aid in prediction of clinical behavior of BAVMs and risk-stratification for clinical management.