Inhibition of Vascular Growth by Modulation of the Anandamide/Fatty Acid Amide Hydrolase Axis

Abstract

Objective: Pathological angiogenesis is a hallmark of various diseases characterized by local hypoxia and inflammation. These disorders can be treated with inhibitors of angiogenesis, but current compounds display a variety of side effects and lose efficacy over time. This makes the identification of novel signaling pathways and pharmacological targets involved in angiogenesis a top priority. Approach and Results: Here, we show that inactivation of FAAH (fatty acid amide hydrolase), the enzyme responsible for degradation of the endocannabinoid anandamide, strongly impairs angiogenesis in vitro and in vivo. Both, the pharmacological FAAH inhibitor URB597 and anandamide induce downregulation of gene sets for cell cycle progression and DNA replication in endothelial cells. This is underscored by cell biological experiments, in which both compounds inhibit proliferation and migration and evoke cell cycle exit of endothelial cells. This prominent antiangiogenic effect is also of pathophysiological relevance in vivo, as laser-induced choroidal neovascularization in the eye of FAAH −/− mice is strongly reduced. Conclusions: Thus, elevation of endogenous anandamide levels by FAAH inhibition represents a novel antiangiogenic mechanism.

Endocannabinoid signaling in glioma

“…Nonetheless, just to mention a few possibilities, cannabinoids impair glioma angiogenesis by inhibiting vascular endothelial growth factor production and signaling, as well as by blunting vascular endothelial cell migration and survival (Blázquez et al, 2003(Blázquez et al, , 2004. Likewise, knocking out the FAAH gene causes antiangiogenic effects in vivo (Rieck et al, 2021). Glioblastoma cells can also hijack activated tumor-associated astrocytes (astrogliosis) to sustain tumor proliferation (O'Brien et al, 2013).…”

DNA methylation signatures on vascular differentiation genes are aberrant in vessels of human cerebral arteriovenous malformation nidus

“…FAAH is involved in hypoxic pulmonary vasoconstriction through the production of various vasoconstrictive eicosanoids [40]. Inactivation of FAAH could attenuate both in vitro and in vivo angiogenesis [25]. We found that more than 60% of CpGs in the gene promoter are hypermethylated in cerebral AVMs.…”

“…To substantiate the DNA hypermethylation, we used DNA isolated from AVM nidus and control tissue (3rd sample) and performed the promoter DNA methylation analysis for the CpG islands of selected genes. We performed bisulfite conversion and sequencing of the selected gene promoters, which are known to involve in vascular development [16,17,25,31,38]. We selected four genes such as ZNF24 (also known (Kox17), AGGF1 (Angiogenic factor with G patch and FHA domains 1), ANKRD65 (Ankyrin repeat domain 65), and FAAH (Fatty acid amid hydrolase) for further validation of DNA hypermethylation on the promoter of these genes [16,17,25,31,38].…”

“…We performed bisulfite conversion and sequencing of the selected gene promoters, which are known to involve in vascular development [16,17,25,31,38]. We selected four genes such as ZNF24 (also known (Kox17), AGGF1 (Angiogenic factor with G patch and FHA domains 1), ANKRD65 (Ankyrin repeat domain 65), and FAAH (Fatty acid amid hydrolase) for further validation of DNA hypermethylation on the promoter of these genes [16,17,25,31,38]. For each gene, we analyzed more than 10 clones.…”

Anandamide Alters Barrier Integrity of Bovine Vascular Endothelial Cells during Endotoxin Challenge

“…Basal expression of CB1 and 2 in this study indicates the involvement of the ECS in non-inflammatory functions of BAEC. Non-inflammatory models utilizing AEA in non-bovine species support the involvement of the ECS in a variety of processes in vascular endothelial cells, such as regulation of vascular tone [ 17 ] and angiogenesis [ 18 ]. Increased gene expression of the cannabinoid receptors following treatment with an antagonist such as LPS was demonstrated in many cell types, not just immune mediating cells.…”