TY - JOUR
T1 - The 5-hydroxytryptamine receptor 1F stimulates mitochondrial biogenesis and angiogenesis in endothelial cells
AU - Dupre, Tess V.
AU - Jenkins, Dorea P.
AU - Muise-Helmericks, Robin C.
AU - Schnellmann, Rick G.
N1 - Funding Information:
We would like to thank Dr. Natalie E. Scholpa at The University of Arizona for creating the graphical abstract. This work was supported by T32 HL007249 and F32 DK120222-01A1 to TVD ( National Institute of Health ); R01 GM084147 ( National Institute of Health ) and 1BX000851 ( Department of Veterans Affairs ) to RGS; and S10 OD011981 ( National Institute of Health shared instrumentation grant for the purchase of the FEI Tecnai Spirit Twin TEM). We would also like to thank Dr. William A. Day at the University of Arizona, Imaging Cores-Life Sciences North for all of his technical help with on the EM experiments.
Publisher Copyright:
© 2019
PY - 2019/11
Y1 - 2019/11
N2 - A hallmark of acute kidney injury (AKI) is vascular rarefication and mitochondrial dysfunction. Promoting vascular recovery following AKI could facilitate kidney repair as the vasculature is responsible for oxygen and nutrient delivery to extravascular tissues. Little is known about mitochondrial biogenesis (MB) in endothelial cells, and the role of 5-HT1F receptor signaling in MB has only been studied in epithelial cells. Our laboratory has shown that stimulating MB through the 5-HT1F receptor promotes recovery from AKI and that 5-HT1F receptor knockout mice have decreased MB and poor renal recovery. We hypothesized that the 5-HT1F receptor plays a role in vascular homeostasis and mediates MB in renal endothelial cells. 5-HT1F receptor knockout mice had decreased renal vascular content, as evidenced by decreased CD31+ endothelial cells and αSMA+ vessels. Human glomerular endothelial cells (HEC) and mouse glomerular endothelial cells (MEC) expressed the 5-HT1F receptor. Treatment of HEC and MEC with 5-HT1F receptor agonists LY344864 or lasmiditan (0–500 nM) induced MB as evidenced by maximal mitochondrial respiration, a marker of MB. HEC and MEC treated with lasmiditan or LY344864 also had increased nuclear- and mitochondrial-encoded proteins (PGC1α, COX-1, and VDAC), and mitochondrial number, confirming MB. Treatment of HEC with LY344864 or lasmiditan enhanced endothelial branching morphogenesis and migration, indicating a role for 5-HT1F receptor stimulation in angiogenic pathways. We propose that stimulation of 5-HT1F receptor is involved in MB in endothelial cells and that treatment with 5-HT1F receptor agonists could restore stimulate repair and recovery following kidney injury.
AB - A hallmark of acute kidney injury (AKI) is vascular rarefication and mitochondrial dysfunction. Promoting vascular recovery following AKI could facilitate kidney repair as the vasculature is responsible for oxygen and nutrient delivery to extravascular tissues. Little is known about mitochondrial biogenesis (MB) in endothelial cells, and the role of 5-HT1F receptor signaling in MB has only been studied in epithelial cells. Our laboratory has shown that stimulating MB through the 5-HT1F receptor promotes recovery from AKI and that 5-HT1F receptor knockout mice have decreased MB and poor renal recovery. We hypothesized that the 5-HT1F receptor plays a role in vascular homeostasis and mediates MB in renal endothelial cells. 5-HT1F receptor knockout mice had decreased renal vascular content, as evidenced by decreased CD31+ endothelial cells and αSMA+ vessels. Human glomerular endothelial cells (HEC) and mouse glomerular endothelial cells (MEC) expressed the 5-HT1F receptor. Treatment of HEC and MEC with 5-HT1F receptor agonists LY344864 or lasmiditan (0–500 nM) induced MB as evidenced by maximal mitochondrial respiration, a marker of MB. HEC and MEC treated with lasmiditan or LY344864 also had increased nuclear- and mitochondrial-encoded proteins (PGC1α, COX-1, and VDAC), and mitochondrial number, confirming MB. Treatment of HEC with LY344864 or lasmiditan enhanced endothelial branching morphogenesis and migration, indicating a role for 5-HT1F receptor stimulation in angiogenic pathways. We propose that stimulation of 5-HT1F receptor is involved in MB in endothelial cells and that treatment with 5-HT1F receptor agonists could restore stimulate repair and recovery following kidney injury.
KW - Angiogenesis
KW - Endothelial cells
KW - Mitochondrial biogenesis
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U2 - 10.1016/j.bcp.2019.113644
DO - 10.1016/j.bcp.2019.113644
M3 - Article
C2 - 31542386
AN - SCOPUS:85072530918
SN - 0006-2952
VL - 169
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
M1 - 113644
ER -