(A) Imaging of typical vascular lesions in moyamoya angiopathy (MMA), arteriovenous malformations (AVM), and cerebral cavernous malformations (CCM). (B) Vascular anomalies develop in different vascular beds that are subject to different hemodynamic environments. MMA lesions appear in intracranial carotid artery bifurcations; AVMs can appear anywhere in the body, including the central nervous system, in internal organs, and subcutaneously; CCMs primarily develop in the brain but can also occur in the spinal cord. Multiple parallel experimental approaches, both in vivo and in vitro, are needed to study the influence of mechanosensitive pathways on vascular malformations. (C) We propose that future studies are needed to interrogate the signaling pathways linked to vascular malformations, including, in vivo and in vitro, gain-of-function mutations (GOF) in the MAPK pathway (mutations observed in MMA, AVMs, and CCMs) and the Notch, KRAS (AVMs), and KLF2/4 (CCMs) pathways, as well as loss-of-function mutations (LOF) in the NO and cGMP pathways (MMA). Figure illustrated by Jose Cabrera (UT Southwestern) and Jeanne Mora Garcia (Potsdam University).