Abstract
BACKGROUND: Arterial restenosis after vascular surgery is a common cause of midterm restenosis and treatment failure. Herein, we aim to investigate the role of microbe-derived butyrate, FFAR2 (free fatty acid receptor 2), and FFAR3 (free fatty acid receptor 3) in mitigating neointimal hyperplasia development in remodeling murine arteries after injury. METHODS AND RESULTS: C57BL/6 mice treated with oral vancomycin before unilateral femoral wire injury to deplete gut microbiota had significantly diminished serum and stool butyrate and more neointimal hyperplasia development after arterial injury, which was reversed by concomitant butyrate supplementation. Deficiency of FFAR3 but not FFAR2, both receptors for butyrate, exacerbated neointimal hyperplasia development after injury. FFAR3 deficiency was also associated with delayed recovery of the endothelial layer in vivo. FFAR3 gene expression was observed in multiple peripheral arteries, and expression was increased after arterial injury. Treatment of endothelial but not vascular smooth muscle cells with the pharmacologic FFAR3 agonist 1-methylcyclopropane carboxylate stimulated cellular migration and proliferation in scratch assays. CONCLUSIONS: Our results support a protective role for butyrate and FFAR3 in the development of neointimal hyperplasia after arterial injury and delineate activation of the butyrate-FFAR3 pathway as a valuable strategy for the prevention and treatment of neointimal hyperplasia.
| Original language | English (US) |
|---|---|
| Article number | e016235 |
| Journal | Journal of the American Heart Association |
| Volume | 9 |
| Issue number | 13 |
| DOIs | |
| State | Published - Jul 7 2020 |
Funding
This work was supported by the National Heart, Lung, and Blood Institute (grants K08HL130601 to Dr Ho and T32HL094293 to Drs Chen and Nooromid); the National Institute of Diabetes and Digestive and Kidney Diseases (grants P30DK42086 and R01DK115221 to Dr Chang and R01DK104927 and R01DK111848 to Dr Layden); the National Center for Advancing Translational Sciences (grant UL1TR001422 to Drs Ho, Chen, and Nooromid); the Department of Veterans Affairs, Veterans Health Administration Office of Research and Development (grant 1I01BX003382 to Dr Layden); Abbott Fund (Fellowship to Drs Chen and Nooromid); American College of Surgeons (Mentored Clinical Scientist Research Career Development Award to Dr Ho); Society for Vascular Surgery (Mentored Clinical Scientist Research Career Development Award to Dr Ho); and Division of Vascular Surgery, Northwestern University Feinberg School of Medicine (Lanterman Vascular Surgery Student Award to K. Shapiro, F. Demsas, and M. Eskandari). Advanced microscopy was performed in the Analytical bioNanoTechnology Core (ANTEC) Facility of the Simpson Querrey Institute at Northwestern University. ANTEC is currently supported by the Soft and Hybrid Nanotechnology Experimental Resource (NSFECCS-1542205). The Simpson Querrey Institute, Northwestern University Office for Research, US Army Research Office, and US Army Medical Research and Materiel Command have also provided funding to develop this facility.
Keywords
- Butyrate
- Neointimal hyperplasia
- Restenosis
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
