AUTHOR=de Jong Alwin , Sier Vincent Q. , Peters Hendrika A. B. , Schilder Natalia K. M. , Jukema J. Wouter , Goumans Marie José T. H. , Quax Paul H. A. , de Vries Margreet R. 

TITLE=Interfering in the ALK1 Pathway Results in Macrophage-Driven Outward Remodeling of Murine Vein Grafts

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=Volume 8 - 2021

YEAR=2022

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2021.784980

DOI=10.3389/fcvm.2021.784980

ISSN=2297-055X

ABSTRACT=Aims Vein grafts are frequently used to bypass coronary artery occlusions. Unfortunately, vein graft disease (VGD) causes impaired patency rates. ALK1 mediates signaling by TGF-β via TGFβR2 or BMP9/10 via BMPR2, which is an important pathway in fibrotic, inflammatory, and angiogenic processes in vascular diseases. A role of the TGF-β pathway in  VGD is previously reported, however, the contribution of ALK1 signaling is not known. Therefore, we investigated ALK1 signaling in VGD in a mouse model for vein graft disease using either genetic or pharmacological inhibition of the Alk1 signaling. 
Methods and results Male ALK1 heterozygous (ALK1+/-), control C57BL/6, as well as hypercholesterolemic ApoE3*Leiden mice, underwent vein graft surgery. Histologic analyses of ALK1+/- vein grafts demonstrated increased outward remodeling and macrophage accumulation after 28 days.  In hypercholesterolemic ApoE3*Leiden mice receiving weekly ALK1-Fc injections, ultrasound imaging showed 3-fold increased outward remodeling compared to controls treated with control-Fc, which was confirmed histologically. Moreover, ALK1-Fc treatment reduced collagen and smooth muscle cells accumulation, increased macrophages by 1.5-fold, and resulted in more plaque dissections. No difference was observed in intraplaque neovessel density. Flow cytometric analysis showed increased systemic levels of Ly6CHigh monocytes in ALK1-Fc treated mice, supported by in vitro increased MCP-1 and IL-6 production of LPS-stimulated and ALK1-Fc-treated murine monocytes and macrophages. 
Conclusion Reduced ALK1 signaling in VGD promotes outward remodeling, increases macrophage influx, and promotes an unstable plaque phenotype.