Endothelial nitric oxide synthase is critical for ischemic remodeling, mural cell recruitment, and blood flow reserve

Yu, Jun; deMuinck, Ebo D.; Zhuang, Zhenwu; Drinane, Mary; Kauser, Katalin; Rubanyi, Gabor M.; Qian, Hu Sheng; Murata, Takahisa; Escalante, Bruno; Sessa, William C.

doi:10.1073/pnas.0501444102

Cited by 288 publications

(288 citation statements)

References 44 publications

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“…As shown in To examine a broader role of Dicer-dependent endothelial miRNAs in additional models of angiogenesis, we investigated whether postnatal angiogenesis was altered in responses to limb ischemia and wound healing. In the first model, arteriectomy of the femoral artery induces arterialization of collateral vessels (arteriogenesis) of the upper limb and increases capillary to skeletal muscle fiber ratio (angiogenesis) in the lower limb (21,22). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

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Dicer-dependent endothelial microRNAs are necessary for postnatal angiogenesis

Suárez

Fernández‐Hernando²,

Yu³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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435

439

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Posttranscriptional gene regulation by microRNAs (miRNAs) is important for many aspects of development, homeostasis, and disease. Here, we show that reduction of endothelial miRNAs by cell-specific inactivation of Dicer, the terminal endonuclease responsible for the generation of miRNAs, reduces postnatal angiogenic response to a variety of stimuli, including exogenous VEGF, tumors, limb ischemia, and wound healing. Furthermore, VEGF regulated the expression of several miRNAs, including the upregulation of components of the c-Myc oncogenic cluster miR-17-92. Transfection of endothelial cells with components of the miR-17-92 cluster, induced by VEGF treatment, rescued the induced expression of thrombospondin-1 and the defect in endothelial cell proliferation and morphogenesis initiated by the loss of Dicer. Thus, endothelial miRNAs regulate postnatal angiogenesis and VEGF induces the expression of miRNAs implicated in the regulation of an integrated angiogenic response.endothelium ͉ VEGF M icroRNAs (miRNAs) are short (Ϸ22 nt) noncoding RNAs derived from long primary transcripts through sequential processing by the enzymes Drosha and Dicer. Dicer-generated miRNAs are incorporated into the RNA-induced silencing complex that mediates miRNA-dependent translational suppression or in some instances cleavage of respective mRNA targets or translational activation (1, 2). The significance of miRNAs in mammalian biology has been dissected by Dicer gene disruption in mice. Mutant and disrupted Dicer alleles caused embryonic lethality associated with a loss of pluripotent stem cells (3) and defective blood vessel formation (4). Tissue-specific inactivation of Dicer has led to the conclusion that Dicer is essential for several processes, for example, limb, lung, and skin morphogenesis, the maintenance of hair follicles, T cell development/ differentiation, and neuronal survival (5-11).The growth of blood vessels is essential for organ growth and tissue repair. During adulthood, most blood vessels remain quiescent to fulfill their main function of conducting nutritive blood flow to organs; however, during pathological events such as tissue ischemia, inflammation, and tumor progression, endothelial cells (ECs) become activated and angiogenesis ensues to provide conduits for blood flow (12). An imbalance in the growth of blood vessels contributes to the pathogenesis of numerous disorders (13), and the growth of vessels is a complex process, requiring a finely tuned balance between numerous stimulatory and inhibitory signals (14). VEGF has been identified as a central mediator of angiogenesis (15). We (16) and others (17) have recently shown that reduction of miRNA levels via Dicer silencing strongly impacts EC functions in vitro, suggesting a critical role for miRNAs in angiogenesis. The role of Dicer-regulated miRNAs in ovarian angiogenesis is suggested by data obtained in mice expressing a global hypomorphic Dicer1 allele, where female mice are infertile because of corpus luteum insufficiency and defective ovarian angiogenesis...

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Section: Resultsmentioning

confidence: 99%

“…RNA extraction and cDNA synthesis was performed as described (16) and detailed in SI Text. Specific primers for VEGFA, VEGF receptor 2, Tie-2, platelet-derived growth factor PDGF-b, MCP-1, IL-1␤, and 18S ribosomal RNA have been described (22).…”

Section: Western Blot Analysismentioning

confidence: 99%

Dicer-dependent endothelial microRNAs are necessary for postnatal angiogenesis

Suárez

Fernández‐Hernando²,

Yu³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

435

439

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“…Viral stocks were stored at -80 o C and the viral titre determined by plaque assay. All other adenoviruses packaged with bovine eNOS (Ad-eNOS), a constitutively active form of human eNOS (Ad-eNOS S1179D) [15,16] or without a transgene (Ad-Null) were amplified and purified as above from previously used viral stocks [12].…”

Section: Construction Propagation and Purification Of Adenoviral Vecmentioning

confidence: 99%

Endothelial nitric oxide synthase induces heat shock protein HSPA6 (HSP70B′) in human arterial smooth muscle cells

2016

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…These include the EC-specific integrins (Friedlander et al 1995;Kurozumi et al 2007;Skuli et al 2009;Desgrosellier and Cheresh 2010;Primo et al 2010), semaphorins (Bielenberg et al 2006;Maione et al 2009), members of the nitric oxide synthase family (Kashiwagi et al 2005(Kashiwagi et al , 2008Yu et al 2005), TGF-b (Liu et al, submitted for publication), and interferon-b (Dickson et al 2007a,c;Taylor et al 2008). In keeping with the notion that it is the balance between pro-and antiangiogenic stimuli that moderates the equilibrium between normal and abnormal vessels, modulation of the activity of these molecules is able to normalize tumor vessels structurally and/or functionally in a variety of tumor models preclinically.…”

Section: Other Angiogenic Moleculesmentioning

confidence: 99%

Vascular Normalization as a Therapeutic Strategy for Malignant and Nonmalignant Disease

Goel

Wong

Jain

2011

Cold Spring Harbor Perspectives in Medicine

294

267

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Pathological angiogenesis-driven by an imbalance of pro-and antiangiogenic signaling-is a hallmark of many diseases, both malignant and benign. Unlike in the healthy adult in which angiogenesis is tightly regulated, such diseases are characterized by uncontrolled new vessel formation, resulting in a microvascular network characterized by vessel immaturity, with profound structural and functional abnormalities. The consequence of these abnormalities is further modification of the microenvironment, often serving to fuel disease progression and attenuate response to conventional therapies. In this article, we present the "vascular normalization" hypothesis, which states that antiangiogenic therapy, by restoring the balance between pro-and antiangiogenic signaling, can induce a more structurally and functionally normal vasculature in a variety of diseases. We present the preclinical and clinical evidence supporting this concept and discuss how it has contributed to successful treatment of both solid tumors and several benign conditions.

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Endothelial nitric oxide synthase is critical for ischemic remodeling, mural cell recruitment, and blood flow reserve

Cited by 288 publications

References 44 publications

Dicer-dependent endothelial microRNAs are necessary for postnatal angiogenesis

Dicer-dependent endothelial microRNAs are necessary for postnatal angiogenesis

Endothelial nitric oxide synthase induces heat shock protein HSPA6 (HSP70B′) in human arterial smooth muscle cells

Vascular Normalization as a Therapeutic Strategy for Malignant and Nonmalignant Disease

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