Endothelial signaling and the molecular basis of arteriovenous malformation

Abstract

Arteriovenous malformations occur when abnormalities of vascular patterning result in the flow of blood from arteries to veins without an intervening capillary bed. Recent work has revealed the importance of the Notch and TGF-β signaling pathways in vascular patterning. Specifically, Notch signaling has an increasingly apparent role in arterial specification and suppression of branching, whereas TGF-β is implicated in vascular smooth muscle development and remodeling under angiogenic stimuli. These physiologic roles, consequently, have implicated both pathways in the pathogenesis of arteriovenous malformation. In this review, we summarize the studies of endothelial signaling that contribute to arteriovenous malformation and the roles of genes implicated in their pathogenesis. We further discuss how endothelial signaling may contribute to vascular smooth muscle development and how knowledge of signaling pathways may provide us targets for medical therapy in these vascular lesions.

Fig. 1

Summary of major endothelial signaling pathways implicated in AVM. AVM signaling in the endothelium is characterized by abnormalities in Notch and TGF-β signaling with growing contributions from other findings that include abnormalities in Ras signaling. Notch signaling defects in AVMs include those from Notch ligand DLL4 and its receptors NOTCH1 and NOTCH4. Notch receptor intracellular domains (NICD) are cleaved upon ligand binding and translocated to the nucleus where they become transcriptionally active with binding partner RBP-J. Functions of this receptor-ligand combination that are pertinent to AVM formation include the determination of arterial character and the suppression of small vessel branching. TGF-β mutants for ALK1, ENG, and SMAD4 correlate with the incidence in AVMs in humans. Mutants for the ALK1 and ENG also produce AVMs in animal models. These TGF-β receptors produce transcriptional activity of SMAD1/5/8 in association with SMAD4 and the activation of SMAD-independent pathways (PI3K, TAK1, RHO, P38, ERK and JNK). Mutants for these genes have abnormal development of VSMCs and marked abnormalities in vascular remodeling. Mutations in p120RasGAP have also been shown to induce AVMs, presumably by failing to limit endothelial cell growth and proliferation