Sprouty1 has a protective role in atherogenesis and modifies the migratory and inflammatory phenotype of vascular smooth muscle cells
Center for Molecular Medicine, MaineHealth Institute for Research
BACKGROUND AND AIMS: Sprouty1 (Spry1) regulates the differentiation of vascular smooth muscle cells (VSMC), and our aim was to determine its role in atherogenesis. A significant proportion of cells within atherosclerotic lesions are derived from migration and pathological adaptation of medial VSMC. METHODS: We used global Spry1 null mouse, and Myh11-Cre, ROSA26-STOP-tdTomato-Spry1 mice to allow for lineage tracing and conditional Spry1 deletion in VSMC. Atherosclerosis was induced by injection of a mutant form of mPCSK9-AAV followed by Western diet. Human aortic VSMC (hVSMC) with shRNA targeting of Spry1 were also analyzed. RESULTS: Global loss of Spry1 increased inflammatory markers ICAM1 and Cox2 in VSMC. Conditional deletion of Spry1 in VSMC had no effect on early lesion development, despite increased Sca1 cells. After 26 weeks of Western diet, mice with VSMC deletion of Spry1 had increased plaque burden, with reduced collagen content and smooth muscle alpha actin (SMA) in the fibrous cap. Lineage tracing via tdTomato marking Cre-recombined cells indicated that VSMC with loss of Spry1 had decreased migration into the lesion, noted by decreased proportions of tdTomato+ and tdTomato+/SMA + cells. Loss-of-function of Spry1 in hVSMC increased mesenchymal and activation markers, including KLF4, PDGFRb, ICAM1, and Cox2. Loss of Spry1 enhanced the effects of PDGFBB and TNFa on hVSMC. CONCLUSIONS: Loss of Spry1 in VSMC aggravated plaque formation at later stages, and increased markers of instability. Our results indicate that Spry1 suppresses the mesenchymal and inflammatory phenotype of VSMC, and its expression in VSMC is protective against chronic atherosclerotic disease.
Yang X, Yang C, Friesel RE, Liaw L. Sprouty1 has a protective role in atherogenesis and modifies the migratory and inflammatory phenotype of vascular smooth muscle cells [published online ahead of print, 2023 Apr 22]. Atherosclerosis. 2023;373:17-28. doi:10.1016/j.atherosclerosis.2023.04.007