Table 1.

Molecular pathways altered by loss-of-function of CCM proteins, and potential pharmacological approaches for the prevention or treatment of CCM disease proposed so far.

Molecular Pathway	KRIT1	CCM2	PDCD10	Pharmacological approaches	Experimental Articles
Adherens junctions	Yes	Yes	n.d.	Antioxidant compounds and autophagy inducers (Tempol, Vitamin D3); inhibitors of the TGF-β and β-catenin pathways (Sulindac sulfide and its analogs)	Glading et al., 2007, Glading and Ginsberg, 2010, Lampugnani et al., 2010, Corr et al., 2012, Gibson et al., 2015, Bravi et al., 2015, Bravi et al., 2016
Autophagy	Yes	Yes	Yes	Autophagy inducers (Rapamycin, Torin1)	Marchi et al., 2015
β-catenin*	Yes	No	Yes	Inhibitors of the β-catenin pathway (Sulindac sulfide and its analogs)	Glading and Ginsberg, 2010, Boulday et al., 2011, Bravi et al., 2015
β1 integrin adhesion	Yes	Yes	n.d.		Zhang et al., 2001, Zawistowski et al., 2002, Faurobert et al., 2013, Liu et al., 2013, Macek Jilkova et al., 2014, Renz et al., 2015
JNK/c-Jun	Yes	n.d.	n.d.	Antioxidant compounds (N-acetylcysteine)	Goitre et al., 2014
FoxO1	Yes	Yes	n.d.	Antioxidant compounds (N-acetylcysteine, Avenanthramide)	Goitre et al., 2010, Moglia et al., 2015, Gibson et al., 2015
Kruppel-like factors (KLF2/4)	Yes	n.d.	n.d.		Cuttano et al., 2016, Renz et al., 2015; Zhou et al., 2015;Zhou et al., 2016
MEKK3	Yes	Yes	Yes		Uhlik et al., 2003, Fisher et al., 2015; Zhou et al., 2015;Cullere et al., 2015, Zhou et al., 2016
Notch/ERK	Yes	n.d.	Yes	Multikinase inhibitors (Sorafenib)	Schulz et al., 2015, Wustehube et al., 2010, You et al., 2013
RhoA/ROCK	Yes	Yes	Yes	Inhibitors of Rho signaling and multi-target compounds (Statins, Fasudil, Tempol, vitamin D3)	Crose et al., 2009, Whitehead et al., 2009, Borikova et al., 2010, Stockton et al., 2010, Zheng et al., 2010, Chan et al., 2011, McDonald et al., 2012, Richardson et al., 2013, Gibson et al., 2015, Zhou et al., 2016
ROS**	Yes	Yes	Yes	Antioxidant compounds and autophagy inducers (N-acetylcysteine, Avenanthramide, Tempol, Vitamin D3, Torin 1, Pt NPs)	Goitre et al., 2010, Goitre et al., 2014, Fidalgo et al., 2012, Moglia et al., 2015, Gibson et al., 2015, Marchi et al., 2015, Moglianetti et al., 2016
STRIPAK***	No	No	Yes		Zheng et al., 2010, Chan et al., 2011, Fidalgo et al., 2012, Voss et al., 2007, Zhang et al., 2013b
TGFβ/BMP and EndMT	Yes	n.d.	Yes	Inhibitors of the TGF-β pathway (Sulindac sulfide and its analogs)	Maddaluno et al., 2013, Bravi et al., 2015, Bravi et al., 2016
VEGF	Yes	n.d.	Yes	VEGFR inhibitors (Semaxanib)	He et al., 2010, Zhu et al., 2010, DiStefano et al., 2014

n.d.—not determined.

^*β-catenin transcriptional activity.

^**ROS production and redox signaling.

^***STRIPAK (striatin-interacting phosphatase and kinase) complex-related pathways.