Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder, characterized by spontaneous recurrent nosebleeds, mucocutaneous telangiectases, and arteriovenous malformations (AVMs) in the brain, lung, liver or GI tract. While reduced expression of either endoglin (ENG) or activin receptor-like kinase 1 (ALK1) has shown to be associated HHT, the precise pathogenetic mechanisms underlying HHT remain elusive; and thus, while palliative care options for HHT patients are well established, curative treatment options for this malady is currently lacking. The ultimate goal of this project is to develop novel therapeutic reagents for treating HHT. We have previously shown that development of skin AVMs in adult mice require secondary insults such as wounding in addition to genetic predisposition by Alk1- or Eng-deficiency. Later we have shown that VEGFA could mimic the wounding effect, and that blockade of VEGFA with neutralizing antibodies was effective in alleviating wound-induced AVMs in the Alk1-iKO models. In agreement with these preclinical findings, bevacizumab has been shown to be effective for epistaxis of HHT patients. VEGFR1 has an antagonistic function for VEGFR2 signaling as a decoy receptor for VEGFA. We initially thought that angiogenic stimulation, e.g. endothelial cell (EC) proliferation, sprouting, migration, and tube formation, via VEGFR2 is the key VEGFA effect for AVM induction. If this were true, VEGFR2 inhibition would have a similar effect with VEGF neutralization for inhibiting AVM formation, while VEGFR1 inhibition would have no or enhancing effect on the wound-induced AVMs. Surprisingly, we found a completely opposite result from this expectation by the R1- and R2-specific inhibition experiment. This result suggests that the inhibition of angiogenic stimulation is not the key effect of VEGFA neutralization for inhibition of AVM formation. It also indicates that VEGFA via VEGFR1 signaling is critical for AVM induction in ALK1-deficient vessels. VEGFR1 is expressed in monocytes/macrophages, and is important for VEGFA- dependent migration of these cells. We showed that ALK1-deficient ECs increased in production of monocytes/macrophage-recruiting chemokines including CCL2, CCL5 and CXCL10, and Angiopoietin2 (ANG2) which plays an important role in activating Tie2-expressing macrophages (TEMs). Finally, we found that macrophage depletion by clodronate liposome dramatically inhibited wound-induced skin AVM development in Alk1-iKO model. The overarching hypothesis of this proposal is that macrophages are essential for the development of AVMs. We will test this hypothesis by utilizing genetic, pharmacological, and cellular approaches.
People with hereditary hemorrhagic telangiectasia (HHT), an inherited rare blood disease, contains arteriovenous malformation (AVM)-arteries and vein are directly connected without capillaries in between them-in various organs in a very high frequency compared with normal individuals. The overall goal of the proposal is to find out `why AVMs develop in HHT patients' and `how we can inhibit formation (and growth) of AVMs' using mouse models. Results from this study may provide important novel insights into fundamental knowledge about the mechanism of disease and development of novel therapeutic modalities for treatment of nosebleeds in HHT patients.
| Kim, Bo-Gyeong; Kim, Yong Hwan; Stanley, Edward L et al. (2017) CXCL12-CXCR4 signalling plays an essential role in proper patterning of aortic arch and pulmonary arteries. Cardiovasc Res 113:1677-1687 |
| Kim, Y H; Kim, M-J; Choe, S-W et al. (2017) Selective effects of oral antiangiogenic tyrosine kinase inhibitors on an animal model of hereditary hemorrhagic telangiectasia. J Thromb Haemost 15:1095-1102 |
