KLF4 and Transcriptional Control of Neovascularization

KLF4 和新血管形成的转录控制

• 批准号: 8578354
• 负责人: Anne Hamik
• 金额: $ 37.72万
• 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 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8578354
• 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; 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; 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; public health relevance; 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、体内平衡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被改变，新血管的形成，通过新生血管生成，允许恶性组织的侵袭性生长。在美国，缺血性血管疾病和癌症分别是导致死亡的第一和第二大原因。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通路具有相当大的科学和治疗意义。kruppel样因子（KLFs）是一个锌指蛋白家族，它调节转录并涉及广泛的生物过程。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4个成员（KLF4）调控肿瘤血管生成和动脉生成。功能获得和功能丧失的研究表明，KLF4调节几个关键的血管生成因子，包括Notch信号通路的成员。内皮特异性过表达KLF4的小鼠肿瘤血管密度增加，但肿瘤大小减小。对肿瘤血管系统的评估表明，KLF4过表达导致无效的血管扩张-血管生成增强，但新血管充血不足，限制了肿瘤的生长。在后肢缺血研究中，内皮细胞KLF4过表达导致股动脉结扎后立即血流量不足（天然侧支功能下降），但在恢复期间侧支重塑增强，血流量迅速与WT动物相等。脑枕侧支血管的评估显示侧支密度降低，与骨骼肌侧支减少的假设一致，导致结扎后立即远端血流受限。脑微血管和气管粘膜毛细血管密度增加；原因尚不清楚，这将是未来研究的主题。KLF4过表达的新生血管表型与Notch信号改变的动物相似。Notch激活在几种新血管形成模式中具有明确的中心作用，Notch调节疗法正在考虑临床应用。这些观察结果为中心假设提供了基础，KLF4是一种新的血管形成调节剂，并作为Notch的上游调节剂发挥作用。为了更好地理解KLF4在这一过程中的确切作用，我们提出了三个目标。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。在目标2中，我们将确定EC KLF4过表达和缺乏对抵押品的作用。在Aim 3中，我们将确定KLF4与Notch之间的精确分子关系。总的来说，这些研究将定义一个新的途径，从核到血管网络，调节血管生长。这些研究结果可能为治疗肿瘤生长或动脉粥样硬化性血管疾病提供有益的新疗法。