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Zhang et al. Vessel Plus 2021;5:48 https://dx.doi.org/10.20517/2574-1209.2021.64 Page 7 of 14

[144]
patients and reduced lesion size and edema in occipital CCM patients . Additionally, it was also observed
that propranolol therapy was effective in immediately stabilizing progressing lesions and preventing future
[163]
bleeds in sporadic CCM patients . Currently, there are two clinical trials actively recruiting patients to
assess lesion burden and clinical events in both familial and symptomatic cerebral cavernous malformation
patients . Statin use has been shown to reduce both nonfatal and fatal strokes, improve functional
[142]
outcomes after ischemic strokes, and reduce coronary death rate and primary and secondary cardiovascular
events [164-167] . A randomized controlled trial involving the use of high-dose statin therapy demonstrated a
[167]
16% decrease in total stroke as well as a five-year absolute risk reduction in fatal and nonfatal strokes .
Despite the promising results seen with statin therapy, a post hoc analysis demonstrated a significant
increase in intracerebral hemorrhage, suggesting that high-dose statin therapy may have contradictory
results [167,168] . These results demonstrate a potential therapeutic use of statins for stroke prevention, but it
should be tailored on an individual patient basis to ensure benefits are maximized while risks are
minimized.

Intriguingly, by examining these candidate drugs, we found an interesting association of these candidates
with the circulating levels of PRG, especially the ones with promising data in animal models. While tempol
can alleviate increased PRG levels induced by dehydroepiandrosterone (DHEA, not statistically
[170]
significant) , vitamin D, as a close physiological partner with PRG , is a strong inhibitor of PRG
[169]
production , suggesting the inhibitory effect of vitamin D/tempol on PRG production. As an inhibitor for
[171]
[172]
TGFβ/β-catenin signaling, sulindac inhibits the expression level of classic PRG receptors (nPRs) , while
[173]
other TGFβ signaling inhibitors, such as K02288 (TGFβ/BMP6) , DMH1 (BMP6) , and SB431542
[174]
(BMP6) , have no effect on PRG levels, suggesting that TGFβ inhibitors might not be a good choice for
[173]
PRG inhibition. Intriguingly, the two most promising candidates, which have been put in clinical trials,
show strong inhibitory effects on PRG levels. While PRG can abolish the beneficial effects of atorvastatin on
[175]
vascular EC functions , statins (atorvastatin, simvastatin, lovastatin, and mevastatin) can directly inhibit
PRG levels [176,177] . Although the molecular mechanisms of its therapeutic action are still unknown, its known
effect of vasoconstriction may be involved [178,179] . Propranolol has been reported to have an inhibitory effect
on PRG levels, from both direct [180,181] and indirect [182,183] evidence, indicating the possibility of decreased PRG
levels in this therapeutic process. Finally, although these two candidate drugs (statins and propranolol)
show great potential for PRG inhibition [176,177,180-183] , they might not be suitable drugs for the treatment and/or
prevention of hemorrhagic CCMs. As common drugs for vascular conditions, both are highly effective and
safe for most people, but they have been shown to have some side effects due to their wide spectrum of
targets. Extensive clinical trials are needed to determine their real benefit and efficacy for hemorrhagic
CCMs.

CONCLUSION
As mentioned above, the haploinsufficiency of CCM genes in microvascular ECs is an essential step in the
pathogenesis of CCM lesions, as demonstrated by in vivo studies with zebrafish [128,129] and Ccms mice
models [130-132] , but it is insufficient to form hemorrhagic CCMs, mimicking the incomplete penetrance seen
in human CCMs. However, when symptoms occur, the disease has typically reached the stage of focal
hemorrhage (likely close to CCM-null condition at the genomic level and/or loss of function at the
proteomic level) with irreversible brain damage. Following this rationale, we believe it could be strategic to
suppress PRG actions on capillary ECs in order to prevent haploinsufficiency of CCM genes reaching
similar levels observed in CCM loss-of-function for the initiation of a hemorrhagic event. Furthermore, it is
not surprising to observe the widespread perturbation of almost all known signaling cascades involved in
angiogenesis due to deficiency of CCMs, since CSC is an essential regulator of microvascular angiogenesis
and perturbation of CSC will lead to disrupted angiogenesis in the most fundamental way [29,128,129,184,185] . For