Search

Summary Members of a disintegrin and metalloproteinases with thrombospondin motif (ADAMTS) family have been implicated in various vascular diseases. However, their functional roles in early embryonic vascular development are unknown. In this study, we showed that Adamts18 is highly expressed at E11.5-E14.5 in cells surrounding the embryonic aortic arch (AOAR) and the common carotid artery (CCA) during branchial arch artery development in mice. Adamts18 deficiency was found to cause abnormal development of AOAR, CCA, and the third and fourth branchial arch appendages, leading to hypoplastic carotid body, thymus, and variation of middle cerebral artery. Adamts18 was shown to affect the accumulation of extracellular matrix (ECM) components, in particular fibronectin (Fn), around AOAR and CCA. As a result of increased Fn accumulation, the Notch3 signaling pathway was activated to promote the differentiation of cranial neural crest cells (CNCCs) to vascular smooth muscle cells. These data indicate that Adamts18-mediated ECM homeostasis is crucial for the differentiation of CNCCs., Graphical abstract, Highlights • Adamts18 is highly expressed during the period of embryonic carotid artery formation • Adamts18 deficiency leads to abnormal AOAR, CCA, MCA branches and carotid appendages • Adamts18 deficiency changes the cerebral infarcted areas in mouse tMCAO model • Adamts18 affects the differentiation of CNCCs to VSMCs by modulating Notch3 pathway, Cell biology; Developmental biology

ADAMTSs (A disintegrin and metalloproteinase with thrombospondin motifs) are a family of 19 secreted zinc metalloproteinases that play a major role in the assembly and degradation of the extracellular matrix (ECM) during development, morphogenesis, tissue repair, and remodeling. ADAMTS18 is a poorly characterized member of the ADAMTS family. Previously, ADAMTS18 was found to participate in the development of female reproductive tract in mice. However, whether ADAMTS18 also plays a role in the development of male reproductive system remains unclear. In this study, Adamts18 mRNA was found to be highly expressed in the basal cells of the developing preputial gland. Male Adamts18 knockout (Adamts18-/-) mice exhibit abnormal preputial gland morphogenesis, including reduced size and sharp outline. Histological analyses of preputial gland from 2-week-old male Adamts18-/- mice showed significant atrophy of the whole gland. Preputial glands from 7 months and older Adamts18-/- mice appeared macroscopic swelling on their surface. Histologically, preputial gland swelling is characterized by tissue fibrosis and thicker keratinized squamous cell layer. Preputial gland lesions in age-matched male Adamts18+/+ mice were barely detected. ADAMTS18 deficiency does not lead to significant changes in morphogenesis of prostate and testis in male mice. These results indicate that ADAMTS18 is required for normal morphogenesis and homeostasis of the preputial gland in male mice.

ADAMTS members have been implicated in vascular diseases by degrading extracellular matrix (ECM), but their functional significance in vascular development remains unknown. We now show that the secreted protease ADAMTS18 is produced by mesenchymal cells and fibroblasts surrounding the embryonic aortic arch (AOAR) and the common carotid artery (CCA). ADAMTS18 deficiency leads to aberrant AOAR and CCA, which further disturbs the development of the 3rd and 4th branchial arch appendages, leading to lack of formation of the carotid body, generation of ectopic and hypoplastic thymus, and variation of intracranial vascular branches of CCA. ADAMTS18 was shown to modulate the ECM abundance around AOAR and CCA, in particular fibronectin (Fn). Adamts18 deficiency lead to Fn accumulation, thus activating the Notch3 signaling pathway to promote the differentiation of cranial neural crest cells (CNCCs) to vascular smooth muscle cells. These data disclose that ADAMTS18-mediated ECM homeostasis is crucial for the differentiation of CNCCs.