<p>We read with great interest the recent publication by Marston and colleagues in Nature Medicine, entitled “Endothelial cell-related genetic variants identify LDL cholesterol-sensitive individuals who derive greater benefit from aggressive lipid lowering” (issue 31, March 2025, pages 963–969). Among their compelling findings, the association between the endothelial cell-specific polygenic risk score (EC-PRS) – which consists of SNPs associated with coronary artery disease – and a reduced risk of migraine headaches stood out, although not being the study’s primary aim. Migraine imposes a substantial individual and socioeconomic burden worldwide. Beyond its neurological manifestations as a primary headache disorder, migraine has increasingly been recognized as an independent and underappreciated cardiovascular risk factor, linked to major cardiovascular and cerebrovascular events. However, the biological underpinnings of this association remain poorly understood, particularly since they do not appear to be mediated through traditional or atherosclerotic pathways, and they are not associated with established cardiovascular risk factors. In this Correspondence, we build upon the findings of Marston et al. and contextualize them within the broader framework of migraine as a neurovascular disorder. Drawing from translational evidence, we propose a conceptual model that integrates findings regarding EC-PRS into the complex biological interplay linking migraine and cardiovascular disease, including coronary artery disease. In doing so, we aim to advance our understanding of migraine not only as a neurological disorder but as a marker of vascular vulnerability with implications for future research regarding personalized cardiovascular prevention, including statin therapy.</p>