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Moreno-Martínez et al. Rare Dis Orphan Drugs J 2024;3:9 https://dx.doi.org/10.20517/rdodj.2023.51 Page 3 of 16

Figure 1. A visual summary of the mechanism detailed in the section of pathophysiology. Image adapted by authors from ref [17,38] . tPA:
Tissue plasmínogen activator; VCAM: vascular cell adhesion molecule; ICAM: intercellular adhesion molecule; Lyso-Gb3:
globotriaosylsphingosine; ROS: reactive oxygen species; NO: nitric oxide; ANG: angiotensin; AT-1: angiotensin type 1 receptor; AT-2:
angiotensin type 2 receptor; MPO: myeloperoxidase; RBC: red blood cells; WBC: white blood cells.

[25]
reviewed . The classical natural T killer cells recognize both Gb3 and lyso-Gb3 as self-antigens presented
[26]
by the major histocompatibility complex to antigen-presenting cells . Recognition of these glycolipids
induces the release of various proinflammatory cytokines such as interferon-gamma, tumor necrosis factor
alpha, and interleukins 4, 5, 9, 10, 13, and 17 [27,28] . This proinflammatory status in patients with FD leads to
endothelial cell activation, inducing a cascade of effects that lead to a prothrombotic state characterized by
dysfunctional platelets, higher secretion of von Willebrand factor, increased release of microparticles, and
the activation of plasminogen [29-32] . Moreover, increased expression of endothelial adhesion molecules has
also been reported [33,34] .

+
2+
Ca -activated K channels
The endothelium controls vascular diameter through the contractile status of the smooth muscle of blood
vessels. This process is mediated by the release of nitric oxide, prostaglandins, and the endothelium-derived
+
2+
hyperpolarizing factor (EDHF). Endothelial hyperpolarization responses are mediated by Ca -activated K
channels (K ) in response to calcium mobilization under shear stress stimulation. The hyperpolarization
Ca
current is then transmitted to the medial muscular layer, inducing muscle relaxation and vasodilation. Gb3
accumulation reduces both K expression and function. Downregulation of pathways that control K
Ca
Ca
expression is observed, including extracellular signal-regulated kinase (ERK) and activating protein-1
(AP-1) pathways, leading to endothelial dysfunction in FD. Moreover, channel activity is inhibited by
decreasing intracellular levels of phosphatidylinositol 3-phosphate, which is a channel agonist [35,36] .
Lyso-Gb3 and the medial muscular layer
Aerts et al. described higher concentrations of plasmatic lyso-Gb3 in patients with FD . A second
[37]
hypothesis of vascular damage in FD considers that the circulating lyso-Gb3 effect on the arterial medial
layer is the main and primary event, inducing smooth muscle hypertrophy, increased shear stress, and vessel
[38]
lumen reduction . It is hypothesized that the increased shear stress induces the upregulation of angiotensin
II; this molecule interacts with the angiotensin 1 receptor (AT1) to produce a complex cascade of events
including the overexpression of adhesion molecules, cytokines, and chemokines. Moreover, AT1 not only
induces a proinflammatory effect on leucocytes, endothelial cells, and vascular smooth muscle cells, but also
reduces nitric oxide formation with a subsequent increase of reactive oxygen species .
[39]

After binding to the AT1 receptor, angiotensin II activates integrin-mediated signaling and overexpression
of the transforming growth factor beta, thereby inducing alterations not only of extracellular matrix quality
and quantity, but also of the cytoskeletal protein composition and filament organization. These changes