*2.3. Intramural Ischemia*

In 1970s, it was proposed that the first determinant of FMD lesions is occlusion of the vasa vasorum, which may induce hypoxia in the arterial wall and transformation of smooth muscle cells into myofibroblasts, typically found in histopathological samples of arteries affected by FMD [19,20]. In particular, Sottiurai and co-workers demonstrated an increase in myofibroblasts and extra-cellular connective tissue of the media, as a result of vasa vasorum obliteration by injection of a thrombine–gelatine mixture into dog femoral arteries [19]. Furthermore, the extracranial internal carotid and external iliac arteries have fewer vasa vasorum than other muscular arteries of similar size, which may make them more susceptible to intramural ischemia [12,15]. However, occlusion of vasa vasorum in patients with FMD has not been demonstrated [20].

## *2.4. Smoking*

Since 1979, smoking has been associated with genesis of FMD and/or its progression in at least 6 studies [15,21–25]. In particular, in a French cohort including 337 patients with FMD, the proportion of current and ever smokers was 30% and 50%, respectively, compared to 18% and 37% in 337 essential hypertensive controls (*p* ≤ 0.001) [24]. Furthermore, current smoking compared to non-current smoking was associated with an earlier FMD onset (43 vs. 51 years, *p* < 0.001) [24], and a higher proportion of renal asymmetry (21% vs. 4%, *p* = 0.001) and number of renal artery revascularization interventions (57% vs. 31%, *p* ≤ 0.001) [24]. Finally, in the US Registry, ever smokers were characterized by an increased proportion of aortic (4.8% vs. 1.5%, *p* < 0.01) [26] but also intracerebral (4.8% vs. 1.7%, *p* < 0.01) aneurysms [25] compared to never smokers.
