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Page 6 of 14 Zhang et al. Vessel Plus 2021;5:48 https://dx.doi.org/10.20517/2574-1209.2021.64

the anticoagulant vascular domain theory and the gut microbiota theory. In the anticoagulant vascular
domain theory, local increases in the endothelial cofactors that generate anticoagulant activated protein C
[136]
contribute to recurrent bleeding in CCM lesions . In the gut microbiota theory, Gram-negative bacterial
signaling through the lipopolysaccharide-activated innate immune receptor, Toll-like receptor 4, promotes
hemorrhagic bleeding in both Ccm1/2 mutant mice, indicating the important roles for the gut microbiome
[134]
and innate immune signaling in the pathogenesis of CCMs . The gut microbiota theory focuses on the
importance of gut microbiota in influencing the interaction direction by inducing an inflammatory gut
milieu, which leads to systemic inflammation that exacerbates the inflammatory response in the brain and
promotes detrimental effects on the BBB . However, lipopolysaccharide-induced Ccms hemorrhagic mice
[137]
demonstrate massive bleeding, leading to lethality at the early stages of life, uncharacteristic of human
CCMs. Nonetheless, neither of the previous theories addresses a key issue of gender discrepancies in CCM
pathogenesis, demanding further evaluation for the underlying mechanisms of hemorrhagic stroke.
Although it is still under debate [4,112,138] , female dominance in CCM patients has long been
suggested [3,113,139,140] , and consensus has been reached on more severe bleeding with worse neurological
outcomes in females [102,139] . This aggressive course of hemorrhagic lesions in females has been proposed to be
a consequence of endocrine influences [3,113,139,140] . Our data demonstrate that enhanced PRG-mPRs signaling,
due to perturbed homeostasis of PRG, leads to BBB disruption, in addition to evidence that long exposure
to hormonal contraceptives increases the risk of cerebral venous sinus thrombosis , which is incongruent
[141]
with the anticoagulant vascular domain theory . Our findings that immunosuppression, caused by sex
[136]
steroid actions in Ccms deficient mice, is associated with CCM bleeding also disagree with the gut
microbiota theory . Therefore, we propose a new paradigm for the mechanisms of initiating hemorrhagic
[134]
CCMs. In nPR(-) ECs, the feedback loops among CSC-mPRs-PRG actions appear to be sensitive, and
perturbation of this intricate balance [Figure 1] , such as hormone therapy or hormonal contraception
[127]
regimens, could result in an increased risk for BBB disruption, especially for human CCMs mutant carriers.
Our new paradigm provides a theory that is in line with clinically observed CCM conditions and
demonstrates the important functions of CSC and non-classic PRG actions in angiogenesis and vascular
health.

CURRENT PHARMACOLOGICAL CANDIDATES TARGETING HEMORRHAGIC CCMS
LINKED TO PRG HOMEOSTASIS
Since the molecular and cellular mechanism of the CmP network in microvascular ECs remains largely
unknown, we recently investigated the CmP signaling network in nPR(-) ECs . Our data indicate that
[127]
nPR(-) ECs are different from nPR(-) TNBC cells (TNBC cells have extremely low CCM expression).
Although nPR(-) ECs share a common core mechanism between the newly defined CmP network and the
CmPn network in breast cancer cells, nPR(-) ECs also showed that steroids can disrupt CSC through their
common targets, mPRs, in a backward fashion (CSC←mPRs←PRG), identical to nPR(+) breast cancer
cells , indicating the significant impact of steroid actions on the stability of CSC.
[51]

Many candidate drugs have been identified and tested in animal models and even small clinical trials [142,143] .
Ironically, the current pool of very diverse candidate drugs were collectively gathered as certain specific
blockers for signaling pathways identified from different experiments using various in vitro and/or in vivo
models [144-157] . Among them, statins and propranolol advanced into clinical trials [142,143,158] , due to some
promising data. Propranolol, one of the most commonly used β-adrenoceptor blockers (beta-blockers), was
[159]
first used to successfully treat another common vascular condition, infantile hemangioma in 2008 , and
additionally with major success in three later cases of giant infantile cerebral cavernomas [160-162] . Utilizing in
vitro, histological, and clinical findings, it was demonstrated that 20-60 mg/day of propranolol not only was
effective in reducing previous hemorrhagic lesions, but it also prevented new hemorrhage in familial CCM