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BMP Receptor Inhibition Enhances Tissue Repair in Endoglin Heterozygous Mice.

International journal of molecular sciences (2021-03-07)
Wineke Bakker, Calinda K E Dingenouts, Kirsten Lodder, Karien C Wiesmeijer, Alwin de Jong, Kondababu Kurakula, Hans-Jurgen J Mager, Anke M Smits, Margreet R de Vries, Paul H A Quax, Marie José T H Goumans
ABSTRACT

Hereditary hemorrhagic telangiectasia type 1 (HHT1) is a severe vascular disorder caused by mutations in the TGFβ/BMP co-receptor endoglin. Endoglin haploinsufficiency results in vascular malformations and impaired neoangiogenesis. Furthermore, HHT1 patients display an impaired immune response. To date it is not fully understood how endoglin haploinsufficient immune cells contribute to HHT1 pathology. Therefore, we investigated the immune response during tissue repair in Eng+/- mice, a model for HHT1. Eng+/- mice exhibited prolonged infiltration of macrophages after experimentally induced myocardial infarction. Moreover, there was an increased number of inflammatory M1-like macrophages (Ly6Chigh/CD206-) at the expense of reparative M2-like macrophages (Ly6Clow/CD206+). Interestingly, HHT1 patients also showed an increased number of inflammatory macrophages. In vitro analysis revealed that TGFβ-induced differentiation of Eng+/- monocytes into M2-like macrophages was blunted. Inhibiting BMP signaling by treating monocytes with LDN-193189 normalized their differentiation. Finally, LDN treatment improved heart function after MI and enhanced vascularization in both wild type and Eng+/- mice. The beneficial effect of LDN was also observed in the hind limb ischemia model. While blood flow recovery was hampered in vehicle-treated animals, LDN treatment improved tissue perfusion recovery in Eng+/- mice. In conclusion, BMPR kinase inhibition restored HHT1 macrophage imbalance in vitro and improved tissue repair after ischemic injury in Eng+/- mice.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Picric acid solution, 1.3% in H2O (saturated)
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Histopaque®-1083, sterile-filtered, density: 1.083 g/mL
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Monoclonal Anti-MAP Kinase, Activated (Diphosphorylated ERK-1&2) antibody produced in mouse, clone MAPK-YT, ascites fluid
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Solketal methacrylate, 50 wt. % in dichloromethane, contains ~280 ppm 4-tert-butylcatechol as inhibitor