The soluble form of a disintegrin and metalloprotease 33 promotes angiogenesis: Implications for airway remodeling in asthma

Background

A disintegrin and metalloprotease (ADAM)–33 is a susceptibility gene for asthma and chronic obstructive pulmonary disease whose function remains unknown.

Objective

Because asthmatic bronchoalveolar lavage fluid contains high levels of soluble ADAM33 (sADAM33), which includes the catalytic domain, we postulated that its release from cell membranes might play functional roles in airway remodeling by promoting angiogenesis.

Methods

The proangiogenic activity of the highly purified catalytic domain of ADAM33 or a catalytically inactive mutant was studied in vitro (Matrigel assay), ex vivo (human embryonic/fetal lung explants) and in vivo (chorioallantoic membrane assay). The regulation of sADAM33 release from cells overexpressing full-length ADAM33 and its biological activity were characterized.

Results

We show that the purified catalytic domain of ADAM33, but not its inactive mutant, causes rapid induction of endothelial cell differentiation in vitro, and neovascularization ex vivo and in vivo. We also show that TGF-β₂ enhances sADAM33 release from cells overexpressing full-length ADAM33 and that this truncated form is biologically active.

Conclusion

The discovery that sADAM33 promotes angiogenesis defines it as a tissue remodeling gene with potential to affect airflow obstruction and lung function independently of inflammation. As TGF-β₂ enhances sADAM33 release, environmental factors that cause epithelial damage may synergize with ADAM33 in asthma pathogenesis, resulting in a disease-related gain of function. This highlights the potential for interplay between genetic and environmental factors in this complex disease.

Key words: ADAM33, asthma, angiogenesis, airway remodeling

Abbreviations used: ADAM, A disintegrin and metalloprotease, BALF, Bronchoalveolar lavage fluid, CAM, Chick embryo chorioallantoic membrane, CHO, Chinese hamster ovary, COPD, Chronic obstructive pulmonary disease, FGF, Fibroblast growth factor, HEK, Human embryonic kidney, HUVEC, Human umbilical vein endothelial cell, SNP, Single nucleotide polymorphism, sADAM33, Soluble a disintegrin and metalloprotease 33, UK, United Kingdom, VEGF, Vascular endothelial growth factor