Endothelial‐specific <scp>CXCL12</scp> regulates neovascularization during tissue repair and tumor progression
C-X-C motif chemokine ligand 12 (CXCL12; Stromal Cell-Derived Factor 1 [SDF-1]), most notably known for its role in embryogenesis and hematopoiesis, has been implicated in tumor pathophysiology and neovascularization. However, its cell-specific role and mechanism of action have not been well characterized. Previous work by our group has demonstrated that hypoxia-inducible factor (HIF)-1 modulates downstream CXCL12 expression following ischemic tissue injury. By utilizing a conditional CXCL12 knockout murine model, we demonstrate that endothelial-specific deletion of CXCL12 (eKO) modulates ischemic tissue survival, altering tissue repair and tumor progression without affecting embryogenesis and morphogenesis. Loss of endothelial-specific CXCL12 disrupts critical endothelial-fibroblast crosstalk necessary for stromal growth and vascularization. Using murine parabiosis with novel transcriptomic technologies, we demonstrate that endothelial-specific CXCL12 signaling results in downstream recruitment of non-inflammatory circulating cells, defined by neovascularization modulating genes. These findings indicate an essential role for endothelial-specific CXCL12 expression during the neovascular response in tissue injury and tumor progression.
Authors
- Maia B. Granoski
- Jagannath Padmanabhan (ORCID: https://orcid.org/0000-0003-1096-6637)
- Michael T. Longaker (ORCID: https://orcid.org/0000-0003-1430-8914)
- Geoffrey C. Gurtner (ORCID: https://orcid.org/0000-0001-6118-7161)
- Hudson C. Kussie (ORCID: https://orcid.org/0000-0001-9877-2313)
- Dominic Henn
- Johannes Riegler (ORCID: https://orcid.org/0000-0002-4713-7392)
- Michael Januszyk (ORCID: https://orcid.org/0000-0002-0313-0973)
- Dominik Duscher (ORCID: https://orcid.org/0000-0002-1775-527X)
- Jonathan P. Yasmeh (ORCID: https://orcid.org/0000-0002-5013-1303)
- Janos A. Barrera (ORCID: https://orcid.org/0000-0001-6811-8337)
- Joseph C. Wu (ORCID: https://orcid.org/0000-0002-6068-8041)
- Michael S. Hu (ORCID: https://orcid.org/0000-0002-5755-910X)
- Dharshan Sivaraj (ORCID: https://orcid.org/0000-0001-7453-0045)
- Kellen Chen (ORCID: https://orcid.org/0000-0002-7023-7850)
- William C. Hahn (ORCID: https://orcid.org/0000-0003-2840-9791)
- Andrew C. Hostler (ORCID: https://orcid.org/0000-0001-9234-7332)
- Zeshaan N. Maan (ORCID: https://orcid.org/0000-0002-7683-1914)
- Ivan N. Vial
- Katharina S. Fischer (ORCID: https://orcid.org/0000-0001-9759-6901)
- Robert Charles Rennert (ORCID: https://orcid.org/0000-0001-6779-3592)
Institutions
- University of Arizona (US)
- Cardiovascular Institute of the South (US)
- Stanford University (US)
Publication Details
- Journal
- The FASEB Journal
- Published
- 2024-12-19
- DOI
- https://doi.org/10.1096/fj.202401307r
- Citations
- 6
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 1.71
Funders
- National Institute of Diabetes and Digestive and Kidney Diseases