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Age-Dependent RGS5 Loss in Pericytes Induces Cardiac Dysfunction and Fibrosis
Anita Tamiato1,2,3, Lukas S Tombor1,2,3, Ariane Fischer1
1Institute of Cardiovascular Regeneration, Center of Molecular Medicine (A.T., L.S.T., A.F., M.M.-R., L.R.V., B.N.T., J.N., S.F.G., M.M., D.R.M., B.S., W.T.A., D.J., S.D., G.L.), Goethe University Frankfurt, Germany.
Insights
Aging impairs cardiac pericytes, reducing vascular stability. Loss of RGS5 in these cells leads to heart dysfunction and fibrosis, highlighting RGS5
Area of Science:
- Cardiovascular Biology
- Aging Research
- Cellular and Molecular Medicine
Background:
- Pericytes are crucial mural cells supporting vascular network stability.
- Aging is a significant risk factor for cardiovascular diseases, but its impact on cardiac pericytes remains unclear.
Purpose of the Study:
- To investigate the effects of aging on cardiac pericytes.
- To elucidate the role of Regulator of G-protein signaling 5 (RGS5) in cardiac pericyte function during aging.
Main Methods:
- Utilized single-nucleus RNA sequencing and histological analysis in murine models.
- Performed in vivo and in vitro loss-of-function studies for RGS5.
- Conducted co-culture experiments with pericytes and fibroblasts.
Main Results:
- Aging decreased pericyte area and capillary coverage in the heart.
- Reduced RGS5 expression was observed in aged cardiac pericytes.
- RGS5 deletion impaired cardiac function, increased fibrosis, and altered pericyte gene expression (e.g., ECM components, TGFB2, PDGFB).
- RGS5-deficient pericyte supernatant activated fibroblasts via a TGFβ2-dependent pathway.
Conclusions:
- RGS5 is identified as a critical regulator of cardiac pericyte function in aging.
- RGS5 deficiency contributes to cardiac dysfunction and myocardial fibrosis, key features of cardiac aging.
Background:
Pericytes are capillary-associated mural cells involved in the maintenance and stability of the vascular network. Although aging is one of the main risk factors for cardiovascular disease, the consequences of aging on cardiac pericytes are unknown.
Methods:
In this study, we have combined single-nucleus RNA sequencing and histological analysis to determine the effects of aging on cardiac pericytes. Furthermore, we have conducted in vivo and in vitro analysis of RGS5 (regulator of G-protein signaling 5) loss of function and finally have performed pericytes-fibroblasts coculture studies to understand the effect of RGS5 deletion in pericytes on the neighboring fibroblasts.
Results:
Aging reduced the pericyte area and capillary coverage in the murine heart. Single-nucleus RNA sequencing analysis further revealed that the expression of Rgs5 was reduced in cardiac pericytes from aged mice. In vivo and in vitro studies showed that the deletion of RGS5 impaired cardiac function, induced fibrosis, and morphological changes in pericytes characterized by a profibrotic gene expression signature and the expression of different ECM (extracellular matrix) components and growth factors, for example, TGFB2 and PDGFB. Indeed, culturing fibroblasts with the supernatant of RGS5-deficient pericytes induced their activation as evidenced by the increased expression of αSMA (alpha smooth muscle actin) in a TGFβ (transforming growth factor beta)2-dependent mechanism.
Conclusions:
Our results have identified RGS5 as a crucial regulator of pericyte function during cardiac aging. The deletion of RGS5 causes cardiac dysfunction and induces myocardial fibrosis, one of the hallmarks of cardiac aging.
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