Table 1.
Mechanisms of several anti-angiogenic and immunomodulatory therapies in HHT.
| Therapy | Angiogenic effects | Evidence | Immuno-modulator | Evidence |
| Tested in patients with HHT | ||||
| Anti-VEGF (G6-31 murine monoclonal antibody) |
+++ | ↑ MVD, ↓ TSP-1, and ↓ Ang-2 in lungs of Eng+/- and Alk1+/- mice, respectively (Ardelean et al., 2014a) ↓ vessel area and density in the skin of Alk1 iKO mouse (Han et al., 2014) |
+ | ↓ inflammation in the colon of DSS-induced Eng+/- colitis (Ardelean et al., 2014b) and the skin of JunB and c-Jun iKO mice (Schonthaler et al., 2009) |
| Thalidomide | ++ |
High dose (200 mg/kg) ↓ vascular area in rabbit cornea (D’Amato et al., 1994) ↓ VEGF, migration and tube formation in EA.hy 926 EC (Komorowski et al., 2006) ↓ VEGFR2 and neuropilin-1 in zebrafish embryos (Yabu et al., 2005) Low dose (75 mg/kg) ↑ pericyte recruitment in neonatal mouse retina (Lebrin et al., 2010) |
++ | ↓ human monocyte-dependent secretion of several cytokines ↑ proliferation and function of circulating human T lymphocytes ↓ number of adhesion molecules in HUVEC ↑ number of NK cells in human multiple myeloma cell lines (Teo, 2005) |
| To be tested in HHT patients | ||||
| Propranolol | ++ | ↓ proliferation and ↑ apoptosis in HUVEC (Xie et al., 2013) ↓ VEGF and MMP-9 in hemangioma-derived EC (Storch and Hoeger, 2010) ↓ endoglin, ACVRL1, PAI-1 in HMEC-1 and HUVEC (Albinana et al., 2012) |
+ | ↑ number of T cells, ↓ NK cell activity in human blood (Maisel et al., 1991) |
| Not yet proposed for HHT patients | ||||
| Tacrolimus | + | ↓ VEGF-induced mouse EC tube formation (Siamakpour-Reihani et al., 2011) ↑ endoglin and Alk1 in HUVEC (Albinana et al., 2011) |
+++ | ↓ T-cell activation in mouse spleen and T cell hybridoma, and in PBMC (Kino et al., 1987; Bierer et al., 1991) |
| IFN-α | + | ↓ EC migration and proliferation in HUVEC (Friesel et al., 1987) |
+++ | Anti-viral in human blood (Neumann et al., 1998), immunomodulation in human blood (Blanco et al., 2001) |
| Infliximab | + | ↓ MVD, VEGF, and EC migration in human intestinal tissue and EC (Rutella et al., 2011) | +++ | Binds soluble and membrane TNF-α in mouse myeloma cells (Scallon et al., 2002) |
DSS, dextran sodium sulfate; HMEC-1, human microvascular endothelial cells; iKO, conditional inducible knockout; MMP-9, matrix metallopeptidase; NK, natural killer cells; PBMC, peripheral blood mononuclear cell; VEGFR2, vascular endothelial growth factor receptor 2.