Prothrombin Loading of Vascular Smooth Muscle Cell–Derived Exosomes Regulates Coagulation and Calcification
Alexander N. Kapustin,Michael Schoppet,Leon J. Schurgers,Joanne L. Reynolds,Rosamund McNair,Alexander Heiss,Willi Jahnen-Dechent,Tilman M. Hackeng,Georg Schlieper,Paul Harrison,Catherine M. Shanahan +10 more
TLDR
In this article, the authors found that Gamma-carboxlyated coagulation proteins are potent inhibitors of vascular calcification suggesting warfarin action on these factors also contributes to accelerated calcification in patients receiving this drug.Abstract:
Objective— The drug warfarin blocks carboxylation of vitamin K–dependent proteins and acts as an anticoagulant and an accelerant of vascular calcification. The calcification inhibitor MGP (matrix Gla [carboxyglutamic acid] protein), produced by vascular smooth muscle cells (VSMCs), is a key target of warfarin action in promoting calcification; however, it remains unclear whether proteins in the coagulation cascade also play a role in calcification.
Approach and Results— Vascular calcification is initiated by exosomes, and proteomic analysis revealed that VSMC exosomes are loaded with Gla-containing coagulation factors: IX and X, PT (prothrombin), and proteins C and S. Tracing of Alexa488-labeled PT showed that exosome loading occurs by direct binding to externalized phosphatidylserine (PS) on the exosomal surface and by endocytosis and recycling via late endosomes/multivesicular bodies. Notably, the PT Gla domain and a synthetic Gla domain peptide inhibited exosome-mediated VSMC calcification by preventing nucleation site formation on the exosomal surface. PT was deposited in the calcified vasculature, and there was a negative correlation between vascular calcification and the levels of circulating PT. In addition, we found that VSMC exosomes induced thrombogenesis in a tissue factor–dependent and PS-dependent manner.
Conclusions— Gamma-carboxlyated coagulation proteins are potent inhibitors of vascular calcification suggesting warfarin action on these factors also contributes to accelerated calcification in patients receiving this drug. VSMC exosomes link calcification and coagulation acting as novel activators of the extrinsic coagulation pathway and inducers of calcification in the absence of Gla-containing inhibitors.read more
Citations
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The biology, function, and biomedical applications of exosomes
TL;DR: The intrinsic properties of exosomes in regulating complex intracellular pathways has advanced their potential utility in the therapeutic control of many diseases, including neurodegenerative conditions and cancer.
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Role of Vascular Smooth Muscle Cell Phenotypic Switching and Calcification in Aortic Aneurysm Formation.
Ploingarm Petsophonsakul,Malgorzata Furmanik,Rachael O. Forsythe,Marc R. Dweck,Geert Willem H. Schurink,Ehsan Natour,Chris P. M. Reutelingsperger,Michael J. Jacobs,Barend Mees,Leon J. Schurgers +9 more
TL;DR: The role of vitamin K and VKDPs that are involved in vascular calcification and aneurysm are addressed, which are known to be disrupted in vascular pathologies.
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The Role of Vascular Smooth Muscle Cells in Arterial Remodeling: Focus on Calcification-Related Processes.
TL;DR: The arterial remodeling processes that govern arterial stiffening, atherosclerosis and calcification are described, with a particular focus on VSMC phenotypic switching.
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Endothelial-Vascular Smooth Muscle Cells Interactions in Atherosclerosis.
TL;DR: The molecular mechanisms underlying the interplay between EC and VSMC that could contribute to atherosclerosis are reviewed and strategic insights for prevention and treatment of atherosclerotic CVD are offered.
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Indoxyl Sulfate and p-Cresyl Sulfate Promote Vascular Calcification and Associate with Glucose Intolerance.
Britt Opdebeeck,Stuart Maudsley,Abdelkrim Azmi,Annelies De Maré,Wout De Leger,Björn Meijers,Björn Meijers,Anja Verhulst,Pieter Evenepoel,Pieter Evenepoel,Patrick C. D'Haese,Ellen Neven +11 more
TL;DR: In CKD, both IS and PCS directly promote vascular calcification via activation of inflammation and coagulation pathways and were strongly associated with impaired glucose homeostasis.
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