TY - JOUR
T1 - Bmp receptor inhibition enhances tissue repair in endoglin heterozygous mice
AU - Bakker, Wineke
AU - Dingenouts, Calinda K.E.
AU - Lodder, Kirsten
AU - Wiesmeijer, Karien C.
AU - de Jong, Alwin
AU - Kurakula, Kondababu
AU - Mager, Hans Jurgen J.
AU - Smits, Anke M.
AU - de Vries, Margreet R.
AU - Quax, Paul H.A.
AU - Goumans, Marie José T.H.
N1 - Funding Information: Author Contributions: Conceptualization, W.B., A.M.S., P.H.A.Q., and M.J.T.H.G.; formal analysis, W.B., C.K.E.D., M.R.d.V., P.H.A.Q., and M.J.T.H.G.; investigation, W.B., C.K.E.D., K.L., K.C.W., K.K., and A.d.J.; H.-J.J.M., providing HHT patient samples; resources, M.J.T.H.G., and P.H.A.Q.; writing—original draft preparation, W.B. and C.K.E.D.; writing—review and editing, W.B., C.K.E.D., A.M.S., H.-J.J.M., M.R.d.V., P.H.A.Q., and M.J.T.H.G.; supervision, M.J.T.H.G. and P.H.A.Q. All authors have read and agreed to the published version of the manuscript Funding: This work was financially supported by the Netherlands Institute for Regenerative Medicine (NIRM, FES0908), the Dutch Heart Foundation (NHS2009B063), and by the Dutch Cardiovascular Alliance (CVON-PHAEDRA-Impact consortium (http://www.phaedraresearch.nl)). Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/2/2
Y1 - 2021/2/2
N2 - 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.
AB - 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.
KW - Endoglin
KW - Hind limb ischemia
KW - Myocardial infarction
KW - Neovascularization
KW - Tissue repair
KW - Transforming growth factor-β
UR - http://www.scopus.com/inward/record.url?scp=85100860054&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/ijms22042010
DO - https://doi.org/10.3390/ijms22042010
M3 - Article
C2 - 33670533
SN - 1661-6596
VL - 22
SP - 1
EP - 19
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 4
M1 - 2010
ER -