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（由申请人提供）：血管生长的调节，使正常组织在发育，体内平衡和伤口修复过程中接受足够的氧气和营养，而内皮的中心功能之一。在肿瘤生长过程中，血管生长的正常调节机制发生了改变，新血管通过发芽血管生成而形成，使恶性组织的积极生长发生。缺血性血管疾病和癌症分别是美国死亡率的主要原因。由于我们对这些疾病状态的治疗不足，因此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兴趣。 Kruppel样因子（KLFS）是调节转录的锌指蛋白家族，并与广泛的生物过程有关。但是，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。功能丧失研究表明，KLF4调节了几种关键的血管生成因素，包括Notch信号通路的成员。 KLF4内皮特异性过表达的小鼠的肿瘤血管密度增加，但肿瘤大小较小。对肿瘤脉管系统的评估表明，KLF4过表达导致无效的高血管性 - 血管生成增强了，但新血管却是液化症，从而限制了肿瘤的生长。在后肢缺血研究中，内皮KLF4的过表达导致股动脉连接后立即血流不足（天然侧支的功能降低），但在恢复期间的侧支重塑增强了，血液流动迅速相当于WT动物。对脑副血管的评估显示，侧支密度降低，与骨骼肌侧支的假定降低一致，这些骨骼肌肉侧支会导致结扎后立即导致有限的远端流动。脑微血管和气管粘膜毛细血管的密度增加；原因尚不清楚，这将是期货研究的话题。 KLF4过表达的新血管化表型让人联想到Notch信号变化的动物中描述的表型。 Notch激活在几种新血管形成模式中具有良好的核心作用，并且正在考虑用于临床使用的Notch调节疗法。这些观察结果为中心假设提供了基础，KLF4是新型的新调节剂，并且是Notch的上游调节剂。为了更好地了解KLF4在此过程中的确切作用，提出了三个目标。在AIM 1中，我们将定义KLF4在发芽血管生成和血管模式中的作用。在AIM 2中，我们将确定EC KLF4过表达和缺乏在抵押品中的作用。在AIM 3中，我们将确定KLF4和Notch之间的精确分子关系。总的来说，这些研究将定义从核到血管网络的新途径，从而调节血管生长。这些研究的结果可能会为治疗肿瘤生长或动脉粥样硬化血管疾病提供有益的新疗法。