PLEKHG1 encodes a guanine nucleotide exchange factor (GEF) that activates the small GTPases RAC1 and CDC42, regulating critical cellular processes including morphology, migration, and endocytosis 1. The protein plays a pivotal role in mechanotransduction, mediating cyclic-stretch-induced reorientation of vascular endothelial cells in response to mechanical stress 2. This vascular endothelial function is particularly relevant to cerebrovascular pathology: PLEKHG1 genetic variants are associated with white matter hyperintensities and small vessel ischemic stroke 3, normal pressure hydrocephalus (rs62434144, OR 1.23, p=1.4×10⁻⁸) 4, and periventricular leukomalacia through disrupted endothelial stress responses 1. Beyond neurovascular disease, PLEKHG1 variants associate with blood pressure regulation across multiple ancestries 5 and early-onset preeclampsia (rs9478812, OR 1.59) 6. Recent Mendelian Randomization analysis identified PLEKHG1 as a key protein linking cerebral small vessel disease to epilepsy through shared vascular and neuroinflammatory mechanisms 7. Epigenetic studies suggest PLEKHG1 methylation changes may drive pediatric ependymoma relapse 8. These findings establish PLEKHG1 as a critical regulator of vascular endothelial integrity with broad relevance to neurovascular and cardiovascular disease pathogenesis.