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Journal of Molecular Histology

, Volume 48, Issue 1, pp 53–61 | Cite as

CRIM1 is necessary for coronary vascular endothelial cell development and homeostasis

  • Swati Iyer
  • Yash Chhabra
  • Tracey J. Harvey
  • Richard Wang
  • Han Sheng Chiu
  • A. G. Smith
  • Walter G. Thomas
  • David J. PennisiEmail author
  • Michael PiperEmail author
Short Communication

Abstract

Endothelial cells form a critical component of the coronary vasculature, yet the factors regulating their development remain poorly defined. Here we reveal a novel role for the transmembrane protein CRIM1 in mediating cardiac endothelial cell development. In the absence of Crim1 in vivo, the coronary vasculature is malformed, the number of endothelial cells reduced, and the canonical BMP pathway dysregulated. Moreover, we reveal that CRIM1 can bind IGFs, and regulate IGF signalling within endothelial cells. Finally, loss of CRIM1 from human cardiac endothelial cells results in misregulation of endothelial genes, predicted by pathway analysis to be involved in an increased inflammatory response and cytolysis, reminiscent of endothelial cell dysfunction in cardiovascular disease pathogenesis. Collectively, these findings implicate CRIM1 in endothelial cell development and homeostasis in the coronary vasculature.

Keywords

Crim 1 Heart Endothelial cells 

Notes

Acknowledgements

We are grateful to Prof. Melissa Little and Prof. Nadia Rosenthal for providing us with the CRIM1 and IGF-1 Ea/Eb expression constructs, respectively. Tie2-Cre mice were a kind gift from Prof. Richard Harvey at the Victor Chang Cardiac Research Institute. This work was funded by grants from the National Health and Medical Research Council to MP (1057751) and DJP (631658), and an ARC Discovery Project to MP (DP160100368). MP holds an Australian Research Council Future Fellowship (FT120100170). SI was supported by a UQ Research Scholarship. Performed experiments: SI, YC, TJH. Analysed data: SI, MP, DJP. Wrote paper: SI, MP. Edited paper: SI, WGT, AGS, MP, DJP.

Supplementary material

10735_2016_9702_MOESM1_ESM.pdf (808 kb)
Supplementary material 1 (PDF 807 kb)

References

  1. Aird WC (2012) Endothelial cell heterogeneity. Cold Spring Harb Perspect Med 2:A006429CrossRefPubMedPubMedCentralGoogle Scholar
  2. Chiu HS, York JP, Wilkinson L, Zhang P, Little MH, Pennisi DJ (2012) Production of a mouse line with a conditional Crim1 mutant allele. Genesis 50:711–716CrossRefPubMedPubMedCentralGoogle Scholar
  3. Delafontaine P, Song Y-H, Li Y (2004) Expression, regulation, and function of Igf-1, Igf-1r, And Igf-1 binding proteins in blood vessels. Arterioscler Thromb Vasc Biol 24:435–444CrossRefPubMedGoogle Scholar
  4. Dyer LA, Pi X, Patterson C (2014) The role of BMPs in endothelial cell function and dysfunction. Trends Endocrinol Metab 25:472–480CrossRefPubMedPubMedCentralGoogle Scholar
  5. Eleuteri E, Di Stefano A, Vallese D, Gnemmi I, Pitruzzella A, Tarro Genta F, Delle Donne L, Cappello F, Ricciardolo FL, Giannuzzi P (2014) Fibrosis markers and CRIM1 increase in chronic heart failure of increasing severity. Biomarkers 19:214–221CrossRefPubMedGoogle Scholar
  6. Fan J, Ponferrada VG, Sato T, Vemaraju S, Fruttiger M, Gerhardt H, Ferrara N, Lang RA (2014) Crim1 maintains retinal vascular stability during development by regulating endothelial cell Vegfa autocrine signaling. Development 141:448–459CrossRefPubMedPubMedCentralGoogle Scholar
  7. Glienke J, Sturz A, Menrad A, Thierauch KH (2002) Crim1 is involved in endothelial cell capillary formation in vitro and is expressed in blood vessels in vivo. Mech Dev 119:165–175CrossRefPubMedGoogle Scholar
  8. Groppe J, Greenwald J, Wiater E, Rodriguez-Leon J, Economides AN, Kwiatkowski W, Affolter M, Vale WW, Belmonte JC, Choe S (2002) Structural basis of BMP signalling inhibition by the cystine knot protein Noggin. Nature 420:636–642CrossRefPubMedGoogle Scholar
  9. Hansson GKMDP (2005) Mechanisms of disease: inflammation, atherosclerosis, and coronary artery disease. New Engl J Med 352:1685–1695CrossRefPubMedGoogle Scholar
  10. Hede MS, Salimova E, Piszczek A, Perlas E, Winn N, Nastasi T, Rosenthal N (2012) E-peptides control bioavailability of Igf-1. PLoS ONE 7:E51152CrossRefPubMedPubMedCentralGoogle Scholar
  11. Hendrickx J, Doggen K, Weinberg EO, Van Tongelen P, Fransen P, De Keulenaer GW (2004) Molecular diversity of cardiac endothelial cells in vitro and in vivo. Physiol Genomics 19:198–206CrossRefPubMedGoogle Scholar
  12. Higashi Y, Quevedo HC, Tiwari S, Sukhanov S, Shai SY, Anwar A, Delafontaine P (2014) Interaction between insulin-like growth factor-1 and atherosclerosis and vascular aging. Front Horm Res 43:107–124PubMedPubMedCentralGoogle Scholar
  13. Hwa V, Oh Y, Rosenfeld RG (1999) The insulin-like growth factor-binding protein (Igfbp) superfamily. Endocr Rev 20:761–787PubMedGoogle Scholar
  14. Iyer S, Chou FY, Wang R, Chiu HS, Raju VKS, Little MH, Thomas WG, Piper M, Pennisi DJ (2016) Crim1 has cell-autonomous and paracrine roles during embryonic heart development. Sci Rep 6:19832CrossRefPubMedPubMedCentralGoogle Scholar
  15. Kisanuki YY, Hammer RE, Miyazaki J-I, Williams SC, Richardson JA, Yanagisawa M (2001) Tie2-Cre transgenic mice: a new model for endothelial cell-lineage analysis in vivo. Dev Biol 230:230–242CrossRefPubMedGoogle Scholar
  16. Kolle G, Georgas K, Holmes GP, Little MH, Yamada T (2000) Crim1, a novel gene encoding a cysteine-rich repeat protein, is developmentally regulated and implicated in vertebrate CNS development and organogenesis. Mech Dev 90:181–193CrossRefPubMedGoogle Scholar
  17. Langenfeld EM, Langenfeld J (2004) Bone morphogenetic protein-2 stimulates angiogenesis in developing tumors. Mol Cancer Res 2:141–149PubMedGoogle Scholar
  18. Larraín J, Bachiller D, Lu B, Agius E, Piccolo S, DeRobertis EM (2000) Bmp-binding modules in chordin: a model for signalling regulation in the extracellular space. Development 127:821–830PubMedPubMedCentralGoogle Scholar
  19. Li WL, Cheng X, Tan XH, Zhang JS, Sun YS, Chen L, Yang X (2005) Endothelial cell-specific expression Of Cre recombinase in transgenic mice. Yi Chuan Xue Bao 32:909–915PubMedGoogle Scholar
  20. Libby P, Ridker PM, Hansson GK (2011) Progress and challenges in translating the biology of atherosclerosis. Nature 473Google Scholar
  21. Pate M, Damarla V, Chi DS, Negi S, Krishnaswamy G (2010) Chapter 5—endothelial cell biology: role in the inflammatory response. In: Gregory SM (ed) Advances in clinical chemistry. Elsevier, AmsterdamGoogle Scholar
  22. Suzuki Y, Montagne K, Nishihara A, Watabe T, Miyazono K (2008) Bmps promote proliferation and migration of endothelial cells via stimulation of Vegf-A/Vegfr2 and angiopoietin-1/Tie2 signalling. J Biochem 143:199–206CrossRefPubMedGoogle Scholar
  23. Wilkinson L, Kolle G, Wen D, Piper M, Scott J, Little M (2003) Crim1 regulates the rate of processing and delivery of bone morphogenetic proteins to the cell surface. J Biol Chem 278:34181–34188CrossRefPubMedGoogle Scholar
  24. Wilkinson L, Gilbert T, Kinna G, Ruta LA, Pennisi D, Kett M, Little MH (2007) Crim1kst264/Kst264 mice implicate Crim1 in the regulation of vascular endothelial growth factor-a activity during glomerular vascular development. J Am Soc Nephrol 18:1697–1708CrossRefPubMedGoogle Scholar
  25. Zhang J-L, Patterson LJ, Qiu L-Y, Graziussi D, Sebald W, Hammerschmidt M (2010) Binding between crossveinless-2 and chordin Von Willebrand factor type C domains promotes bmp signaling by blocking chordin activity. PLoS ONE 5:E12846CrossRefPubMedPubMedCentralGoogle Scholar
  26. Zhang Y, Fan J, Ho JWK, Hu T, Kneeland SC, Fan X, Xi Q, Sellarole MA, De Vries WN, Lu W, Lachke SA, Lang RA, John SWM, Maas RL (2016) Crim1 regulates integrin signaling in murine lens development. Development 143:356–366CrossRefPubMedPubMedCentralGoogle Scholar
  27. Zimmerman LB, De Jesus-Escobar JM, Harland RM (1996) The spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4. Cell 86:599–606CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  1. 1.School of Biomedical SciencesThe University of QueenslandBrisbaneAustralia
  2. 2.Queensland Brain InstituteThe University of QueenslandBrisbaneAustralia

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