Abstract
Hemorrhagic hereditary telangiectasia (HHT) type 2 patients have increased activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway in telangiectasia. The main objective is to evaluate the activation of the PI3K pathway in cutaneous telangiectasia of HHT1 patients. A cutaneous biopsy of a digital hand telangiectasia was performed in seven HHT1 and eight HHT2 patients and compared with six controls. The study was approved by the Clinical Research Ethics Committee of our center. A histopathological pattern with more dilated and superficial vessels that pushed up the epidermis was identified in HHT patients regardless of the type of mutation and was associated with older age, as opposed to the common telangiectasia pattern. The mean proliferation index (Ki-67) was statistically higher in endothelial cells (EC) from HHT1 than in controls. The percentage of positive EC for pNDRG1, pAKT, and pS6 in HHT1 patients versus controls resulted in higher values, statistically significant for pNDRG1 and pS6. In conclusion, we detected an increase in EC proliferation linked to overactivation of the PI3K pathway in cutaneous telangiectasia biopsies from HHT1 patients. Our results suggest that PI3K inhibitors could be used as novel therapeutic agents for HHT.
Highlights
Hereditary hemorrhagic telangiectasia (HHT) or Rendu–Osler–Weber syndrome (ORPHA774) is a vascular autosomal-dominant germline disease, with an incidence of 1:6000 [1,2]
Using heterozygous activin receptor-like kinase 1 (ALK1) mouse retinas and cultured endothelial cells (EC), we found that loss of ALK1 leads to increased EC proliferation as a result of the overactivation of phosphatidylinositol 3-kinase (PI3K) signaling
Several types of variants were observed in the ENG gene: two nonsense, one frameshift, and one missense, as well as one large deletion involving exons
Summary
Hereditary hemorrhagic telangiectasia (HHT) or Rendu–Osler–Weber syndrome (ORPHA774) is a vascular autosomal-dominant germline disease, with an incidence of 1:6000 [1,2]. Mutations in endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1) genes are detected in approximately. 85% of cases submitted to molecular diagnosis for clinical suspicion of HHT, and cause HHT1 and HHT2, respectively [2,3]. Both proteins are expressed in endothelial cells (ECs). Endoglin is an auxiliary co-receptor that promotes BMP9 signaling through the activin receptor-like kinase 1. Both proteins contribute to the signaling hub formed by BMP9–Endoglin–ALK1–Smad with high impact in EC proliferation, migration, and survival during angiogenesis [4]. The loss of function of endoglin and ALK1 proteins provokes an anomalous vascular overgrowth [4,5]
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