Work

Genetic and pharmacological targeting of mTORC1 in mouse models of arteriovenous malformation expose non-cell autonomous signalling in HHT

Year: 2024

Type: article

Abstract: Arteriovenous malformations (AVMs) are abnormal high flow shunts between arteries and veins with major negative impact on the cardiovascular system. Inherited loss-of-function (LOF) mutations in endoglin, encoding an endothelial cell (EC) expressed co-receptor for BMP9/10, causes the disease HHT1/Osler-Weber-Rendu, characterized by bleeding and AVMs. Here we observe increased activity of the downstream signalling complex mTORC1 within the retinal vasculature of HHT mouse models. To investigate its importance in AVM biology, concerning subvascular action, cell specificity, signalling strength and kinetics we combine timed genetic and antibody-based models of HHT with genetic mTORC1 inhibition or activation through EC specific deletion of Rptor or Tsc1. Results demonstrate that EC mTORC1 activation is secondary to endoglin LOF and mainly a consequence of systemic effects following AVM. While genetic EC inhibition of mTORC1 only showed tendencies towards reduced AVM severity, EC overactivation counterintuitively reduced it, implying that mTORC1 must be within a certain range to facilitate AVM. Complete inhibition of mTORC1 signalling by rapamycin provided the strongest therapeutic effect, pointing to potential involvement of RAPTOR-independent pathways or AVM-promoting effects of non-ECs in this pathology.

Source: Angiogenesis

DOI: 10.1007/s10456-024-09961-5

Authors: Antonio Queiro-Palou, Yi Jin, Lars Jakobsson

Institution: Karolinska Institutet

Language: English

Topic: Vascular Anomalies and Treatments

Subfield: Genetics

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $5,090