ABNORMAL VASCULAR CELL INTERACTIONS IN BRAIN AVMs

该计划的项目2所代表的一系列研究建立在临床和基础科学家之间的合作基础上。我们将描述与脑动静脉畸形（BAVM）相关的血管生物学现象。该项目的优势在于并行机制研究加上大量新病例入组，从而允许临床数据与生物组织测定数据相关。这种联系是独特和重要的，因为BAVM代表了广泛的生理学改变。将研究三种主要类型的组织：（1）BAVM病灶（n=80），一种异常扩张的血管缠结，形成直接高流量动静脉分流，无介入毛细血管床;（2）相邻结构正常的脑（n=40）;和（3）癫痫手术的对照脑（n=40）。两 将使用人类手术标本和细胞培养系统。我们的假设如下：（1）与（B）Tie-2 /血管生成素（Ang）通路相比，BAVM代表了（a）内皮细胞（EC）有丝分裂原、血管内皮生长因子（VEGF）的相对增加，Tie-2 /血管生成素（Ang）通路募集和维持内皮周围支持结构（例如，平滑肌细胞和 周细胞）。这种不平衡最初导致微分流形成（流量增加）。当VEGF受体（VEGF-R）激活正在进行时，增加的Ang-2信号有利于BAVM生长。BAVM的生长和消退需要调节细胞外基质。(2)基质金属蛋白酶（MMP）降解BAVM血管中的细胞外基质。细胞外基质过度降解将使BAVM血管易于破裂（=颅内出血）。(3)从机制上讲，超生理水平的Ang-2，不受Ang-1的反对，下调Tie-2在BAVM中的表达，作为反馈机制的一部分，或通过阻断Ang-1对Tie-2的刺激。重要性：阐明BAVM中异常血管生成所涉及的途径有助于识别临床相关的生物学现象，其机制可以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BAVM的临床行为和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.