KLF4 and Transcriptional Control of Neovascularization

KLF4 和新血管形成的转录控制

• 批准号: 8877619
• 负责人: Anne Hamik
• 金额: $ 39.03万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8877619
• 关键词: Acute; Anastomosis - action; Angiogenic Factor; Animal Experiments; Animals; Area; Atherosclerosis; Binding; Blood Vessels; Blood capillaries; Blood flow; Cell Nucleus; Cells; Cerebrum; Clinical; Collateral Circulation; Complex; Coronary; Coupled; Data; Development; Disease; Distal; Endothelial Cells; Endothelium; Event; Family; Family member; Fetal Death; Fetal Development; Foundations; Gene Targeting; Genetic; Genetic Transcription; Goals; Growth; Health; Hindlimb; Homeostasis; Individual; Inflammatory; Injury; Investigation; Ischemia; Lateral; Ligands; Ligation; Malignant - descriptor; Malignant Neoplasms; Modeling; Molecular; Mus; Myocardial Infarction; Neoplasms in Vascular Tissue; Normal tissue morphology; Notch Signaling Pathway; Nutrient; Outcome; Oxygen; Pathologic Neovascularization; Pathway interactions; Pattern; Perfusion; Perinatal; Peripheral arterial disease; Phenotype; Physiologic Neovascularization; Process; Proteins; Recovery; Regulation; Retinal Neoplasms; Role; Series; Signal Pathway; Signal Transduction; Skeletal Muscle; Stroke; Therapeutic; Tissues; Transcriptional Regulation; Tumor Angiogenesis; Tumor Tissue; United States; Up-Regulation; Vascular Diseases; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vascular System; Wound Healing; Zinc Fingers; angiogenesis; artery occlusion; base; bevacizumab; blood vessel development; capillary; density; femoral artery; in vivo; interest; loss of function; mature animal; member; mortality; mouse model; neovascularization; notch protein; novel; overexpression; postnatal; promoter; protein complex; receptor; research study; shear stress; transcription factor; tumor; tumor growth

DESCRIPTION (provided by applicant): Regulation of blood vessel growth so that normal tissues receive sufficient oxygen and nutrients during development, homeostasis, and wound repair while is one of the central functions of the endothelium. During tumor growth, normal regulatory mechanisms of vessel growth are altered, and new vessels formation, via sprouting angiogenesis, occur allowing aggressive growth of the malignant tissue. Ischemic vascular disease and cancer are the first and second, respectively, leading cause of mortality in the United States. As our treatments for these disease states are insufficient, a better understanding of the cellular signaling pathways that control them is of considerable scientific and therapeutic interest. Kruppel-like Factors (KLFs) are a family of zinc finger proteins that regulate transcription and are implicated in a wide spectrum of biologic processes. However, a role for the KLF family in blood vessel growth is unknown. Based on our preliminary studies, we find that the 4th member of this family (KLF4) regulates tumor angiogenesis and arteriogenesis. Gain- and loss-of-function studies reveal that KLF4 regulates several critical angiogenic factors including members of the Notch signaling pathway. Mice with endothelial-specific overexpression of KLF4 have increased tumor blood vessel density, but smaller tumor size. Assessment of the tumor vasculature suggests that KLF4 overexpression leads to ineffective hypervascularity- angiogenesis is enhanced , but the new vessels are hypoperfused, limiting tumor growth. In hindlimb ischemia studies endothelial KLF4 overexpression leads to poor blood flow immediately post femoral artery ligation (decreased function of native collaterals), but enhanced collateral remodeling during the recovery period, with blood flow quickly becoming equal to WT animals. Assessment of cerebral pial collateral vessels shows decreased collateral density, consistent with the presumed decrease in skeletal muscle collaterals that cause the limited distal flow immediately post ligation. Cerebral microvessels and tracheal mucosal capillaries are increased in density; the cause of this is yet unknown and will be a topic for futue studies. The neovascularization phenotypes seen with KLF4 overexpression are reminiscent of those described in animals with altered Notch signaling. Notch activation has a well-established central role in several modes of neovascularization, and Notch-modulating therapies are under consideration for clinical use. These observations provide the foundation for the central hypothesis the KLF4 is a novel regulator of neovascularization, and functions as an upstream regulator of Notch. To better understand the precise role of KLF4 in this process, three aims are proposed. In Aim 1, we will define the role of KLF4 in sprouting angiogenesis and vascular patterning. In Aim 2 we will determine the role of EC KLF4 overexpression and deficiency on collateralization. In Aim 3, we will determine the precise molecular relationship between KLF4 and Notch. Collectively, these studies will define a novel pathway, from nucleus to vascular network, that regulates blood vessel growth. The results of these studies may provide new therapies beneficial in the treatment of tumor growth or atherosclerotic vascular disease.

描述（申请人提供）：调节血管生长，使正常组织在发育、稳态和伤口修复过程中获得足够的氧气和营养，是内皮细胞的核心功能之一。在肿瘤生长过程中，血管生长的正常调节机制发生改变，并通过发芽血管生成形成新血管，从而导致恶性组织的侵袭性生长。缺血性血管疾病和癌症分别是美国第一和第二大死亡原因。由于我们对这些疾病状态的治疗还不够，更好地了解控制它们的细胞信号传导途径具有相当大的科学和治疗意义。 Kruppel 样因子 (KLF) 是调节转录的锌指蛋白家族，与多种生物过程有关。然而，KLF 家族在血管生长中的作用尚不清楚。根据我们的初步研究，我们发现该家族的第四个成员（KLF4）调节肿瘤血管生成和动脉生成。功能获得和功能丧失研究表明，KLF4 调节多种关键的血管生成因子，包括 Notch 信号通路的成员。内皮特异性过度表达 KLF4 的小鼠肿瘤血管密度增加，但肿瘤尺寸较小。对肿瘤脉管系统的评估表明，KLF4 过度表达会导致无效的血管过多——血管生成增强，但新血管灌注不足，从而限制了肿瘤生长。在后肢缺血研究中，内皮 KLF4 过度表达导致股动脉结扎后立即血流不良（天然侧枝循环功能下降），但在恢复期间增强侧枝重塑，血流量很快变得与 WT 动物相等。脑软膜侧支血管的评估显示侧支密度降低，与推测的骨骼肌侧支减少一致，导致结扎后立即限制远端血流。脑微血管及气管粘膜毛细血管密度增高；其原因尚不清楚，将成为未来研究的主题。 KLF4 过表达所观察到的新血管形成表型让人想起在 Notch 信号传导改变的动物中所描述的表型。 Notch 激活在多种新血管形成模式中具有明确的核心作用，Notch 调节疗法正在考虑用于临床。这些观察结果为 KLF4 是新血管形成的新型调节剂并作为 Notch 的上游调节剂发挥作用的中心假设提供了基础。为了更好地理解 KLF4 在此过程中的确切作用，提出了三个目标。在目标 1 中，我们将定义 KLF4 在血管生成和血管模式形成中的作用。在目标 2 中，我们将确定 EC KLF4 过度表达和缺陷对抵押的作用。在目标 3 中，我们将确定 KLF4 和 Notch 之间的精确分子关系。总的来说，这些研究将定义一条从细胞核到血管网络的新途径，调节血管生长。这些研究的结果可能提供有益于治疗肿瘤生长或动脉粥样硬化性血管疾病的新疗法。