Talin-dependent integrin activation is required for endothelial proliferation and postnatal angiogenesis
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ORIGINAL PAPER
Talin‑dependent integrin activation is required for endothelial proliferation and postnatal angiogenesis Fadi E. Pulous1 · Jamie C. Carnevale1 · Zaki Al‑Yafeai2 · Brenna H. Pearson2 · Jamie A. G. Hamilton1 · Curtis J. Henry1 · A. Wayne Orr2,3,4 · Brian G. Petrich1 Received: 8 May 2020 / Accepted: 20 October 2020 © Springer Nature B.V. 2020
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. Keywords Talin1 · Angiogenesis · Proliferation · Integrin
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10456-020-09756-4) contains supplementary material, which is available to authorized users. * Brian G. Petrich [email protected] 1
Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA, USA
2
Department of Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport, LA, USA
3
Department of Cell Biology and Anatomy, LSU Health Sciences Center, Shreveport, LA, USA
4
Pathology and Translational Pathobiology, LSU Health Sciences Center, Shreveport, LA, USA
Endothelial cells (ECs) form a tight, continuous monolayer of cells to form the luminal surface of blood vessels. ECs form adhesive contacts with the basement membrane at cellmatrix adhesions and are connected to
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