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Talin-dependent integrin activation is required for endothelial proliferation and postnatal angiogenesis

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Abstract

Integrin activation contributes to key blood cell functions including adhesion, proliferation and migration. An essential step in the cell signaling pathway that activates integrin requires the binding of talin to the β-integrin cytoplasmic tail. Whereas this pathway is understood in platelets in detail, considerably less is known regarding how integrin-mediated adhesion in endothelium contributes to postnatal angiogenesis. We utilized an inducible EC-specific talin1 knock-out mouse (Tln1 EC-KO) and talin1 L325R knock-in mutant (Tln1 L325R) mouse, in which talin selectively lacks the capacity to activate integrins, to assess the role of integrin activation during angiogenesis. Deletion of talin1 during postnatal days 1–3 (P1-P3) caused lethality by P8 with extensive defects in retinal angiogenesis and widespread hemorrhaging. Tln1 EC-KO mice displayed reduced retinal vascular area, impaired EC sprouting and proliferation relative to Tln1 CTRLs. In contrast, induction of talin1 L325R in neonatal mice resulted in modest defects in retinal angiogenesis and mice survived to adulthood. Interestingly, deletion of talin1 or expression of talin1 L325R in ECs increased MAPK/ERK signaling. Strikingly, B16-F0 tumors grown in Tln1 L325R adult mice were 55% smaller and significantly less vascularized than tumors grown in littermate controls. EC talin1 is indispensable for postnatal development angiogenesis. The role of EC integrin activation appears context-dependent as its inhibition is compatible with postnatal development with mild defects in retinal angiogenesis but results in marked defects in tumor growth and angiogenesis. Inhibiting EC pan-integrin activation may be an effective approach to selectively target tumor blood vessel growth.

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  • 18 November 2020

    The author name A. Wayne Orr was tagged correctly in XML

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Acknowledgements

We thank the following investigators for generously providing mice used in these studies: David Critchley and Susan Monkley (Tln1fl/fl mice) and Ralf Adams (Cdh5-CreERT2 mice). We are also grateful for support from Children’s Healthcare of Atlanta and the Emory University Integrated Cellular Imaging Core.

Funding

This work was supported in part by National Institutes of Health National Heart, Lung, and Blood Institute grant HL117061 (B.G. Petrich), HL098435, HL133497, HL141155 (A.W. Orr), F31HL136194 (F.E. Pulous), Emory University School of Medicine Bridge Funding Grant 00098174, the Winship Invest$ Pilot Grant 00099018, Aflac Pilot Grant 00080676, Mark Foundation for Cancer Research Grant 18-031-ASP (C.J. Henry), and ASH Minority Hematology Graduate Award 0000055928 (J. A. G. Hamilton).

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Authors and Affiliations

  1. Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA, USA

    Fadi E. Pulous, Jamie C. Carnevale, Jamie A. G. Hamilton, Curtis J. Henry & Brian G. Petrich

  2. Department of Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport, LA, USA

    Zaki Al-Yafeai, Brenna H. Pearson & A. Wayne Orr

  3. Department of Cell Biology and Anatomy, LSU Health Sciences Center, Shreveport, LA, USA

    A. Wayne Orr

  4. Pathology and Translational Pathobiology, LSU Health Sciences Center, Shreveport, LA, USA

    A. Wayne Orr

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  1. Fadi E. Pulous
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Pulous, F.E., Carnevale, J.C., Al-Yafeai, Z. et al. Talin-dependent integrin activation is required for endothelial proliferation and postnatal angiogenesis. Angiogenesis 24, 177–190 (2021). https://doi.org/10.1007/s10456-020-09756-4

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