PI3K (Phosphatidylinositol 3-Kinase) Activation and Endothelial Cell Proliferation in Patients with Hemorrhagic Hereditary Telangiectasia Type 1

Iriarte, Adriana; Figueras, Agnés; Cerdà, Pau; Mora, J.; Jucglà, Anna; Penín, R.M.; Viñals, Francesc; Riera‐Mestre, Antoni

doi:10.3390/cells8090971

Cited by 42 publications

(43 citation statements)

References 37 publications

(75 reference statements)

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“…Therefore, other unknown mechanisms should be involved in gender differences. New insights in the underlying mechanisms may help to gain a better understanding of HHT pathophisiology and angiogenesis process, and could help to develop new treatments or drug repositioning [46][47][48][49].…”

Section: Discussionmentioning

confidence: 99%

Gender differences in hereditary hemorrhagic telangiectasia severity

Mora-Luján

Iriarte

Alba

et al. 2020

Orphanet J Rare Dis

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Background: Gender differences in organ involvement and clinical severity have been poorly described in hereditary hemorrhagic telangiectasia (HHT). The aim of this study was to describe differences in the severity of HHT manifestations according to gender. Methods: Severity was measured according to Epistaxis Severity Score (ESS), Simple Clinical Scoring Index for hepatic involvement, a general HHT-score, needing for invasive treatment (pulmonary or brain arteriovenous malformations-AVMs-embolization, liver transplantation or Young's surgery) or the presence of adverse outcomes (severe anemia, emergency department-ED-or hospital admissions and mortality). Results: One hundred forty-two (58.7%) women and 100 (41.3%) men were included with a mean age of 48.9 ± 16.6 and 49 ± 16.5 years, respectively. Women presented hepatic manifestations (7.1% vs 0%) and hepatic involvement (59.8% vs 47%), hepatic AVMs (28.2% vs 13%) and bile duct dilatation (4.9% vs 0%) at abdominal CT, and pulmonary AVMs at thoracic CT (35.2% vs 23%) more often than men. The Simple Clinical Scoring Index was higher in women (3.38 ± 1.2 vs 2.03 ± 1.2), and more men were considered at low risk of harboring clinically significant liver disease than women (61% vs 25.3%). These differences were mantained when considering HHT1 and HHT2 patients separetely. Duodenal telangiectasia were more frequent in men than women (21% vs 9.8%). Invasive treatments were more frequently needed in women (28.2% vs 16%) but men needed attention at the ED more often than women (48% vs 28.2%), with no differences in ESS, HHT-score, anemia hospital admissions or mortality. Conclusions: HHT women showed more severe hepatic involvement than men, also among HHT1 and HHT2 patients. Women had higher prevalence of pulmonary AVMs and needed invasive procedures more frequently, while men needed attention at the ED more often. These data might help physicians to individualize HHT patients follow-up.

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Section: Discussionmentioning

confidence: 99%

Gender differences in hereditary hemorrhagic telangiectasia severity

Mora-Luján

Iriarte

Alba

et al. 2020

Orphanet J Rare Dis

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“…Endoglin (encoded by ENG) is an auxiliary co-receptor at the endothelial cell surface that promotes BMP9 signaling through the activin receptor-like kinase 1 (ALK1; encoded by ACVRL1). Both proteins contribute to the signaling hub formed by BMP9-Endoglin-ALK1-Smad with a high impact in angiogenesis [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Current HHT genetic overview in Spain and its phenotypic correlation: data from RiHHTa registry

Sánchez-Martínez

Iriarte

Mora-Luján

et al. 2020

Orphanet J Rare Dis

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Background: Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular disease with autosomal dominant inheritance. Disease-causing variants in endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1) genes are detected in more than 90% of cases submitted to molecular diagnosis. Methods: We used data from the RiHHTa (Computerized Registry of Hereditary Hemorrhagic Telangiectasia) registry to describe genetic variants and to assess their genotype-phenotype correlation among HHT patients in Spain. Results: By May 2019, 215 patients were included in the RiHHTa registry with a mean age of 52.5 ± 16.5 years and 136 (63.3%) were women. Definitive HHT diagnosis defined by the Curaçao criteria were met by 172 (80%) patients. Among 113 patients with genetic test, 77 (68.1%) showed a genetic variant in ACVRL1 and 36 (31.8%) in ENG gene. The identified genetic variants in ACVRL1 and ENG genes and their clinical significance are provided. ACVRL1 mutations were more frequently nonsense (50%) while ENG mutations were more frequently, frameshift (39.1%). ENG patients were significantly younger at diagnosis (36.9 vs 45.7 years) and had pulmonary arteriovenous malformations (AVMs) (71.4% vs 24.4%) and cerebral AVMs (17.6% vs 2%) more often than patients with ACVRL1 variants. Patients with ACVRL1 variants had a higher cardiac index (2.62 vs 3.46), higher levels of hepatic functional blood tests, and anemia (28.5% vs 56.7%) more often than ENG patients. Conclusions: ACVRL1 variants are more frequent than ENG in Spain. ACVRL1 patients developed symptomatic liver disease and anemia more often than ENG patients. Compared to ACVRL1, those with ENG variants are younger at diagnosis and show pulmonary and cerebral AVMs more frequently.

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“…In postnatal retina, BMP9/10 ligand blockade and endothelial-specific homozygous ALK1 inactivation induces excessive angiogenesis via activating VEGF and PI3K/Akt signaling (Ola et al, 2016;Ruiz et al, 2016;Alsina-Sanchis et al, 2018). Pharmacological or genetic inhibition of PI3K rather than VEGFR could abolish ALK1-induced vascular hyperplasia in vivo, confirming that PI3K/Akt is the core mechanism downstream of BMP9/10-ALK1 signaling in maintaining vascular quiescence (Alsina-Sanchis et al, 2018;Ola et al, 2018;Iriarte et al, 2019; Figure 3).…”

Section: Hereditary Hemorrhagic Telangiectasia (Hht)mentioning

confidence: 87%

The Roles of TGF-β Signaling in Cerebrovascular Diseases

Zhang

Yang

2020

Front. Cell Dev. Biol.

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Cerebrovascular diseases are one of the leading causes of death worldwide, however, little progress has been made in preventing or treating these diseases to date. The transforming growth factor-β (TGF-β) signaling pathway plays crucial and highly complicated roles in cerebrovascular development and homeostasis, and dysregulated TGF-β signaling contributes to cerebrovascular diseases. In this review, we provide an updated overview of the functional role of TGF-β signaling in the cerebrovascular system under physiological and pathological conditions. We discuss the current understanding of TGF-β signaling in cerebral angiogenesis and the maintenance of brain vessel homeostasis. We also review the mechanisms by which disruption of TGF-β signaling triggers or promotes the progression of cerebrovascular diseases. Finally, we briefly discuss the potential of targeting TGF-β signaling to treat cerebrovascular diseases.

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PI3K (Phosphatidylinositol 3-Kinase) Activation and Endothelial Cell Proliferation in Patients with Hemorrhagic Hereditary Telangiectasia Type 1

Cited by 42 publications

References 37 publications

Gender differences in hereditary hemorrhagic telangiectasia severity

Gender differences in hereditary hemorrhagic telangiectasia severity

Current HHT genetic overview in Spain and its phenotypic correlation: data from RiHHTa registry

The Roles of TGF-β Signaling in Cerebrovascular Diseases

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