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Page 2 of 14 Zhang et al. Vessel Plus 2021;5:48 https://dx.doi.org/10.20517/2574-1209.2021.64

Keywords: Cerebral cavernous malformations, CCM signaling complex, progesterone, membrane progesterone
receptors, CSC-mPRs-PRG signaling network, blood-brain barrier

INTRODUCTION
Cerebral cavernous malformations (CCMs) are characterized by abnormally dilated intracranial
[1-5]
microvascular capillaries that result in increased susceptibility to stroke . Familial CCMs are an autosomal
dominant condition . Three genes have been identified as culprits of most familial CCM cases [7-16] : CCM1
[1,6]
at 7q11-22 , CCM2 at 7p15-23 , and CCM3 at 3q25.2-27 . These genes encode CCM proteins, including
[12]
[11]
[12]
KRIT1 as CCM1 [13,16-19] , MGC4607 as CCM2 , and PDCD10 as CCM3 [21,22] , that have been shown to interact
[20]
with each other and form a core CCM triplex. In this triplex, CCM1 and CCM3 compete to bind to PTB
domains of CCM2 . This core CCM triplex, in turn, interacts with other proteins [22,24-27] to form a complex
[23]
referred to as the CCM signaling complex (CSC) [28,29] . Although the majority of CCMs gene mutation
carriers are largely asymptomatic due to the incomplete penetrance of CCMs, when symptoms do occur, the
disease has typically reached a serious stage of focal hemorrhage with irreversible brain damage. Currently,
the invasive neurosurgical removal of CCM lesions is the only option for treatment, despite the recurrence
of hemorrhagic events after surgery. Therefore, there is a grave need to understand the angiogenic functions
of CSC in maintaining neurovascular integrity. Uncovering the mechanistic underpinnings of this
signalosome may provide novel avenues for developing stroke prevention and vascular therapy techniques.
Based on the various perturbed angiogenic signaling cascades reported, there have been many proposed
candidate drugs, potentially targeting angiogenic-relevant signaling pathways dysregulated by loss of
function of one of the CCM proteins, which might not be enough to correct the pathological phenotype,
hemorrhagic CCMs. In this article, we propose a new concept for the assurance of CSC stability to prevent
the devastating outcome of hemorrhagic CCMs.

FEMALE SEX STEROID HORMONES AND STROKE
The overall lifetime risk of stroke is similar between women and men ; however, postmenopausal women
[30]
are at a much greater stroke risk, compared to premenopausal women. Women generally bear a notable
lower risk of stroke during earlier life, until reaching their middle age, doubling the risk of stroke in women
10 years post-menopause [31-33] . This drastically increased stroke risk in women is caused by declining levels
of circulating sex steroid hormones in the blood, especially estrogen [31,34] . Estrogen has been widely
recognized as a beneficial factor for the integrity of vasculature [35-42] due to its actions on nuclear/membrane
estrogen receptors (nERs/mERs) [37,43-45] in vascular smooth muscle cells [46,47] and endothelial cells [38,48-50] .
Furthermore, sex steroids, estrogen, androgen, and glucocorticoid, have been evaluated, but no significant
perturbation of CSC was found involving any of these sterols . Increased stroke risk associated with altered
[51]
levels of circulating female sex hormones has been well defined for several major female physiological
events, including post-menopause, pregnancy, oral contraceptive regimens, and hormone replacement
therapy . It needs to be mentioned that the physiological changes during pregnancy, caused by the altered
[52]
levels/composition of circulating female sex hormones, is a major risk factor for stroke in women [53-60] .
Epidemiologic data in the United States indicate that approximately 87% of strokes are ischemic, and the
remaining 13% are hemorrhagic strokes [61-63] . Interestingly, hemorrhagic stroke is the most dominant type
(up to 74%) of strokes during pregnancy, much higher than that in the general population [64-71] , suggesting
an important correlation between altered progesterone (PRG) levels [Table 1] and elevated hemorrhagic
[72]
stroke risk .

Although women and men have measurable amounts of PRG in the bloodstream, the levels and patterns of
change of circulating PRG differ. Circulating PRG is approximately 0.5 ng/mL for males, while PRG levels