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HHT for the hematologist
with multiple receptor complexes of the TGF-β receptor complex and also modulates ALK1 and ALK5.27,28 Circulating BMP9 has been demonstrated to bind strongly with endoglin and ALK1 receptors found abundantly in the surface membrane of endothelial cells.29 ALK1 recep- tors phosphorylate SMAD1/5/8 in the cytoplasm to form the SMAD1/5/8-SMAD4 complex that translocates to the nucleus to promote normal endothelial cell proliferation and smooth muscle migration. In contrast, the ALK5 path- way works through SMAD2/3 to inhibit normal endothe- lial cell proliferation and smooth muscle migration.27,28,30 The result is contrasting responses that balance endothe- lial proliferation, angiogenesis and smooth muscle migra- tion.
In patients with HHT, mutations in endoglin, ALK1, or one of several other proteins in this pathway alter the nor- mal endothelial response. In HHT1, the ENG mutation leads to reduced endoglin, ALK1 and ALK5 signaling; in HHT2, the ALK1 mutation causes reduced ALK1 signaling alone. Mice with one functioning copy of Eng or Acvrl1 show clinical signs of HHT.31 The haploinsufficiency of these proteins along with a second hit, such as tissue injury, infection or hypoxia, likely cause the focal vascular lesions of HHT1 and HHT2 as reduced levels of endoglin or ALK1 cannot maintain the balance needed for normal
blood vessel formation (recruitment of smooth muscle cells and proliferation of endothelial cells).26,32 Decreased TGF-β transcription normally mediated through this path- way, therefore, disrupts the vascular integrity and smooth muscle differentiation of the endothelium resulting in an abnormal cytoskeleton and fragile small vessels.
Vascular endothelial growth factor, an endothelial-spe- cific factor for angiogenesis, is of major interest in diseases of vascular malformation and is elevated in HHT patients.33 VEGF production is stimulated by ALK5 (and SMAD2 through activation of ALK5) and inhibited by ALK1 (and SMAD1 through activation of ALK1).34 Therefore, any mutation along the ALK1 pathway (BMP9, ACVRL1, ENG, MADH4) results in elevation of VEGF through reduced ALK1 pathway signaling. VEGF drives many of the pathogenic manifestations of HHT, as nor- malizing VEGF has been shown to prevent AVMs in Acvrl1-deficient mice.35 This may be secondary to reduced angiogenic stimuli and reduction of feeding arteries from blocking the VEGF that would normally develop and maintain arteriovenous shunts.
Other factors that may contribute to the severity of dis- ease include repeated injury and chronic inflammation in keeping with the two-hit hypothesis and stimulation of the ALK1 signaling pathway. An abnormal endothelium
Figure 1. Molecular pathophysiology of hereditary hemorrhagic telangiectasia (HHT). Physiological signaling via ALK1 and ALK5 receptors (activated via binding BMP9 and TGFβ) results in activation of different SMAD pathways, which converge at SMAD4 resulting in transcription of genes involved in angiogenesis.30 In HHT, mutations perturb signaling through ALK1 via mutations in the ALK1 receptor itself, its ligand BMP9, or its modulator, the glycoprotein membrane receptor endoglin. The result is decreased signaling through ALK1 and increased signaling through ALK5, perturbing normal endothelial proliferation and smooth muscle cell migration. Reduced ALK1 signaling and increased ALK5 signaling also result in higher vascular endothelial growth factor (VEGF) levels, causing increased endothelial prolifer- ation (which may be exacerbated by stress or hypoxia), resulting in arteriovenous malformations (AVMs), telangiectasias, and the manifestations of HHT.
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