Inhibition of the Semaphorin 4D-Plexin-B1 axis prevents calcification in vascular smooth muscle cells
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Vascular calcification is common in cardiovascular diseases includingatherosclerosis, and is associated with an increased riskof pathological events and mortality. Some semaphorin familymembers play an important role in atherosclerosis. In the presentstudy, we show that Semaphorin 4D/Sema4D and itsPlexin-B1 receptor were significantly upregulated in calcifiedaorta of a rat chronic kidney disease model. Significantly higherSema4D and Plexin-B1 expression was also observed duringinorganic phosphate-induced calcification of vascular smoothmuscle cells. Knockdown of Sema4D or Plexin-B1 genes attenuatedboth the phosphate-induced osteogenic phenotype of vascularsmooth muscle cells, through regulation of SMAD1/5 signaling,as well as apoptosis of vascular smooth muscle cells,through modulation of the Gas6/Axl/Akt survival pathway. Takentogether, our results offer new insights on the role of Sema4Dand Plexin-B1 as potential therapeutic targets against vascularcalcification.
Abstract
Vascular calcification is common in cardiovascular diseases includingatherosclerosis, and is associated with an increased riskof pathological events and mortality. Some semaphorin familymembers play an important role in atherosclerosis. In the presentstudy, we show that Semaphorin 4D/Sema4D and itsPlexin-B1 receptor were significantly upregulated in calcifiedaorta of a rat chronic kidney disease model. Significantly higherSema4D and Plexin-B1 expression was also observed duringinorganic phosphate-induced calcification of vascular smoothmuscle cells. Knockdown of Sema4D or Plexin-B1 genes attenuatedboth the phosphate-induced osteogenic phenotype of vascularsmooth muscle cells, through regulation of SMAD1/5 signaling,as well as apoptosis of vascular smooth muscle cells,through modulation of the Gas6/Axl/Akt survival pathway. Takentogether, our results offer new insights on the role of Sema4Dand Plexin-B1 as potential therapeutic targets against vascularcalcification.
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