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Zhang et al. Vessel Plus 2021;5:48 Vessel Plus
DOI: 10.20517/2574-1209.2021.64

Review Open Access

Calm the raging hormone - a new therapeutic

strategy involving progesterone-signaling for
hemorrhagic CCMs

Jun Zhang, Johnathan S. Abou-Fadel

Departments of Molecular & Translational Medicine (MTM), Texas Tech University Health Science Center El Paso (TTUHSCEP),
El Paso, TX 79905, USA.
Correspondence to: Dr. Jun Zhang, Department of Molecular and Translational Medicine (MTM), Texas Tech University Health
Science Center El Paso, 5001 El Paso Drive, El Paso, El Paso, TX 79905, USA. E-mail: jun.zhang2000@gmail.com
How to cite this article: Zhang J, Abou-Fadel JS. Calm the raging hormone - a new therapeutic strategy involving progesterone-
signaling for hemorrhagic CCMs. Vessel Plus 2021;5:48. https://dx.doi.org/10.20517/2574-1209.2021.64

Received: 15 Apr 2021 First Decision: 2 Jun 2021 Revised: 12 Jun 2021 Accepted: 24 Jun 2021 First online: 5 Jul 2021
Academic Editors: Aaron S. Dumont, Jawahar L. Mehta, Alexander D. Verin Copy Editor: Yue-Yue Zhang Production Editor:
Yue-Yue Zhang

Abstract
Cerebral cavernous malformations (CCMs), one of the most common vascular malformations, are characterized by
abnormally dilated intracranial microvascular capillaries resulting in increased susceptibility to hemorrhagic stroke.
As an autosomal dominant disorder with incomplete penetrance, the majority of CCMs gene mutation carriers are
largely asymptomatic, but, when symptoms occur, the disease has typically reached the stage of focal hemorrhage
with irreversible brain damage, while the molecular “trigger” initiating the occurrence of CCM pathology remain
elusive. Currently, the invasive neurosurgery removal of CCM lesions is the only option for the treatment, despite
the recurrence of worse symptoms frequently occurring after surgery. Therefore, there is a grave need for the
identification of molecular targets for therapeutic treatment and biomarkers as risk predictors for hemorrhagic
stroke prevention. Based on the various perturbed angiogenic signaling cascades mediated by the CCM signaling
complex (CSC) reported, there have been many proposed candidate drugs, targeting potentially 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 review, we describe a new paradigm for
the mechanism of hemorrhagic CCM lesions and propose a new concept for the assurance of CSC stability to
prevent the devastating outcome of hemorrhagic CCMs.

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing,
adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as
long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and
indicate if changes were made.

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