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Evaluation of Chloride Intracellular Channels 4 and 1 Functions in Developmental and Pathological Angiogenesis

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Evaluation of Chloride Intracellular Channels 4 and 1 Functions in Developmental and Pathological Angiogenesis Evaluation of Chloride Intracellular Channels 4 and 1 Functions in Developmental and Pathological Angiogenesis Jennifer Jean Tung Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy under the Executive Committee of the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2012 © 2012 Jennifer Jean Tung All Rights Reserved ABSTRACT Evaluation of Chloride Intracellular Channels 4 and 1 Functions in Developmental and Pathological Angiogenesis Jennifer Jean Tung Members of the chloride intracellular channel (CLIC) protein family have been implicated as regulators of tubulogenesis, a critical step in the formation of new blood vessels during angiogenesis. We sought to determine CLIC4 and CLIC1 function in angiogenesis. We hypothesized that CLIC4 and CLIC1 act in endothelial lumen formation and promote both developmental and pathological angiogenesis. Using in vitro studies, we found that CLIC4 promotes endothelial proliferation, network formation, capillary-like sprouting, and lumen formation. In vivo, Clic4 knockout mice display a mild defect in retinal vascular development and an apparent decrease in retinal macrophage content. By implanting murine tumor cells in Clic4 knockout mice, we discovered that Clic4 affects the establishment of lung metastases. Endothelial and smooth muscle cell content of tumors are comparable to wild type, but overall vessel architecture is altered. In studying CLIC1, we found that CLIC1 knockdown results in reduced endothelial proliferation, directed migration, network formation, and capillary-like sprouting in vitro . In vivo analysis revealed no apparent angiogenic phenotype in the developing retinas of Clic1 knockout mice. We developed Clic4 -/-;Clic1 -/- double mutant embryos, which were unable to develop beyond 9.5 dpc. Whole mount staining of Clic4 -/-;Clic1 -/- 9.5 dpc embryos for vasculature revealed an angiogenic defect, most notable along the intersomitic vessels and in the brain. Endothelial content is reduced in Clic4;Clic1 double knockout embryos, and double nullizygous embryos were growth retarded. Preliminary histological analysis of Clic4 -/-;Clic1 -/- 9.5 dpc embryos suggests altered aortic development, reduced proliferation, and increased apoptosis. I conclude that CLIC4 and CLIC1 function in endothelial proliferation and morphogenesis and that Clic4 and Clic1 are required for embryonic development. Together, our findings indicate that CLIC4 and CLIC1 are important in developmental angiogenesis and should be considered in elucidating the molecular mechanisms of tubulogenesis. Contents List of Figures ……………………………………………………………………... iii List of Tables ……………………………………………………………………... vi Acknowledgements ……………………………………………………………... vii Chapter 1. Introduction …………………………………………………….... 1 1.1 Overview of angiogenesis in development and pathology ..…….… 1 1.2 Mechanisms of tubulogenesis ….………………………………...... 2 1.3 Chloride intracellular channels ....……………………….………… 4 1.4 Evidence for CLIC function in angiogenesis ..….…………………. 6 1.5 Figures ...…………………………………………………………... 11 Chapter 2. CLIC4 is involved in endothelial cell proliferation and morphogenesis in vitro …………………………………………... 13 2.1 Abstract .…………………………………………………………… 13 2.2 Introduction .……………………………………………………….. 14 2.3 Altered CLIC4 expression does not affect endothelial cell migration .………………………………………………………….. 17 2.4 CLIC4 expression promotes endothelial cell proliferation ..…...…. 18 2.5 CLIC4 promotes endothelial capillary-like network formation …... 19 2.6 Altered CLIC4 expression affects capillary-like sprouting and lumen formation .……………………………………………….….. 21 2.7 Discussion .………………………………………………………… 22 2.8 Figures ……………………………………………………….......... 26 2.9 Additional discussion ..…………………………………………….. 40 2.10 Supplementary figures ...…………………………………………... 41 Chapter 3. Generation and characterization of Clic4 knockout mice ….….. 47 3.1 Abstract .…………………………………………………………… 47 3.2 Introduction .……………………………………………………….. 48 3.3 Clic4 targeting scheme …………………………………………….. 49 3.4 Clic4 knockout mice are underrepresented, but viable and fertile .…………………………………………………………. 51 3.5 Clic4 knockout mice display subtle defects in postnatal angiogenesis and may have reduced macrophage content in the developing retina ….………………………………………… 52 3.6 Clic4 knockout may enhance tumor growth and metastasis ..…..... 53 3.7 Discussion …………..…………………………………………...… 55 3.8 Figures ………………………………………………..…………… 59 3.9 Tables ……………………………………………………………… 69 i Chapter 4. Chloride intracellular channel 1 functions in endothelial cell growth and migration ………………………………….…… 70 4.1 Abstract .…………………………………………………………… 70 4.2 Introduction .……………………………………………………….. 71 4.3 Generation of endothelial cell lines with stable CLIC1 knockdown .………………………………………………………... 73 4.4 CLIC1 knockdown inhibits endothelial cell growth .……………… 74 4.5 CLIC1 knockdown inhibits endothelial migration .……………….. 75 4.6 CLIC1 influences expression of select integrins on endothelial cells .……………………………………………...…… 76 4.7 CLIC1 plays a role in capillary-like network formation .……..….. 77 4.8 Reduced CLIC1 expression affects capillary-like sprouting and branching .………………………………………………….….. 78 4.9 Discussion .………………………………………………………… 79 4.10 Figures ……………....…………………………………………….. 83 4.11 Additional discussion .…………………………………………...… 95 4.12 Supplementary figures …………………………………………….. 97 4.13 Supplementary tables ……………………………………………… 103 Chapter 5. Clic4 and Clic1 are required for embryonic development …….. 104 5.1 Abstract …………………………………………………………… 104 5.2 Introduction ……………………………………………………….. 105 5.3 Generation of Clic4 and Clic1 double mutants …………………… 107 5.4 Clic4 -/-;Clic1 -/- double knockout mice are embryonic lethal at 9.5 dpc ………………………………………………..…... 108 5.5 Clic4 -/-;Clic1 -/- double knockout mice display aberrant vascular development ………………………………………………109 5.6 Aortic development and proliferation may be altered in Clic4 -/-;Clic1 -/- embryos ………………………………………….. 110 5.7 Discussion …………………………………………………………. 111 5.8 Figures …………………………………………………………….. 116 5.9 Tables ……………………………………………………………… 134 Chapter 6. Conclusions and future directions ………………………………. 136 Chapter 7. Materials and methods …………………………………………... 147 Bibliography ………………………………………………………………………. 164 Appendix Regulation of cardiovascular development and integrity by the heart of glass–cerebral cavernous malformation protein pathway …………………………………….. 176 ii List of Figures Chapter 1. Fig 1.1 Cell hollowing and cord hollowing models for tubulogenic mechanisms …………………………………………... 11 Chapter 2 Fig 2.1 Establishing CLIC4 knockdown and overexpression in endothelial cells ……………………………………………….... 26 Fig 2.2 CLIC4 expression has no effect on endothelial cell migration ….... 28 Fig 2.3 CLIC4 expression promotes endothelial cell proliferation ……....... 30 Fig 2.4 Altering CLIC4 expression affects endothelial cell survival ……… 32 Fig 2.5 CLIC4 expression promotes in vitro endothelial network formation …......................................................................... 34 Fig 2.6 Reduced CLIC4 expression inhibits endothelial network formation independent of its proliferative defect ………………….. 36 Fig 2.7 CLIC4 expression affects capillary-like sprouting in vitro ………...38 Supp Fig 2.1 Clic1 and Clic4 are most highly expressed in cultured endothelial cells …………………………………………… 41 Supp Fig 2.2 CLIC4 expression affects endothelial morphogenesis in a three-dimensional extracellular matrix ……………..… 43 Supp Fig 2.3 CLIC4 expression does not affect ion conductance at the plasma membrane in HEK 293 cells …………………... 45 Chapter 3 Fig 3.1 Diagram of Clic4 targeting strategy and ES cell targeting confirmation …………………………………………....... 59 Fig 3.2 Confirmation of Clic4 knockout …………………………………... 61 Fig 3.3 Clic4 homozygous knockout mice are phenotypically normal at 9.5 dpc ………………………………………………...…63 iii Fig 3.4 Clic4 knockout mice show reduced retinal vasculature and macrophage content …………………………………………... 65 Fig 3.5 Tumorigenesis is enhanced by Clic4 knockout ………………........ 67 Chapter 4 Fig 4.1 Establishing human endothelial cell lines with CLIC1 knockdown ………………………………………………… 83 Fig 4.2 CLIC1 knockdown has mild effects on viability and significantly inhibits endothelial cell growth ……………………… 85 Fig 4.3 Reduced CLIC1 expression inhibits endothelial migration ……….. 87 Fig 4.4 CLIC1 expression plays a role in the expression of various integrins …………………………………………………… 89 Fig 4.5 Knocked down CLIC1 expression inhibits capillary-like network formation and branching morphogenesis ………………… 91 Fig 4.6 Reduced CLIC1 expression affects capillary-like sprouting and branching …………………………………………… 93 Supp Fig 4.1 Confirmation of CLIC4 overexpression and CLIC1 knockdown ………………………………………… 97 Supp Fig 4.2 Partial rescue of the CLIC1 knockdown network formation defect by CLIC4 ………………………………... 99 Supp Fig 4.3 Loss of Clic1 does not affect postnatal retinal angiogenesis ……………………………………………….. 101 Chapter 5 Fig 5.1 Clic4;Clic1 double knockout embryos present cardiac edema at 10.5 dpc …………………………………………………. 116 Fig 5.2 Embryos missing three Clic alleles are represented at 10.5 dpc ….. 118 Fig 5.3 Clic4 +/+ ;Clic1 -/- 9.5 dpc embryos are indistinguishable from Clic4 +/+ ;Clic1 +/+ embryos …………………………………... 120 Fig 5.4 In utero death for Clic4 -/-;Clic1 -/- embryos occurs at 9.5 dpc with growth retardation and an angiogenic defect …...……………. 122 iv Fig 5.5 Endothelial content is reduced in Clic4 -/-;Clic1 -/- developing embryos ……………………………………………….. 124 Fig 5.6 Aortic development may be altered in Clic4 -/-;Clic1 -/-
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