SAVE · Shear Stress Induced Arterial and Venous Specification through Piezo1
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2018-07-01 → 2020-11-18
- EU contribution
- €195,455
- Participants
- 1
- Scheme
- MSCA-IF
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Results in brief
Shear Stress Induced Arterial and Venous Specification through Piezo1
Arteriovenous malformations (AVMs) are congenital disorders, which consist of an abnormal connection between arteries and veins, and are caused by defects during vascular remodelling. If arteries and veins do not differentiate and remodel properly, the result is congenital disorders, such as AVMs, with an estimated prevalence of 18 in 100,000, of which an astounding two-thirds occur before the age of 40. Although most patients with AVM appear asymptomatic, they have a significantly increased risk of stroke and aneurysm. This occurs because the vein of an AVM is exposed to abnormally high arterial blood pressure, causing it to expand and eventually rupture. Moreover, AVMs can form anywhere in the body and some of them can be quite large and difficult to remove with conventional surgery. My innovative investigation of the involvement of the ion channel Piezo1 in AV specification provides a new perspective in gaining knowledge to understand the molecular mechanism underlying vascular development and the onset of diseases such AVMs, possibly providing future new potential therapeutic avenues in order to reduce the area affected by AVMs prior to surgical operation. The overall objectives of this SAVE research proposal are: 1) Show that Piezo1 activation by shear stress leads to calcium signal that activates Notch signalling. 2) Demonstrate that Piezo1 mediates arterial-venous differentiation by activating Notch signalling in response to haemodynamic forces generated by the passage of blood flow i.e. shear stress. 3) Demonstrate that ablation of Piezo1 results in AVM development due to impairment of Notch signalling activation.
Data: CORDIS, © European Union
Project objective
Arteriovenous malformations (AVMs) are characterised by abnormal connections between arteries and veins due to defects during vascular remodelling. Although often asymptomatic, AVMs can cause intense pain and patients affected present higher risk for strokes and aneurysms. Hereditary AVMs have a prevalence of 18 in 100000 people causing a two-fold increase in mortality in patients younger than 60 years of age. Hereditary AVMs are linked to defective Notch/BMP signalling, however they represent less than 10% of cases. The majority of AVMs do not present genetic mutations and remain idiopathic. Asides Notch/BMP signalling, vascular responses to haemodynamic forces generated by blood flow are crucial regulators of blood vessel formation. The passage of fluid results in physical forces on the endothelium, i.e. shear stress, which activate signalling cascades inside the cells necessary for vascular remodelling. Endothelial cells sense shear stress through proteins localised on their plasmatic membrane. The calcium channel Piezo1 is required for shear stress induced calcium signalling and its ablation resulted in serious vascular defects. Both shear stress and calcium signalling are known to affect the activation of Notch, a pathway essential during the process of arterial-venous specification and vascular remodelling. Therefore we hypothesise that Piezo1 plays a crucial role in arterial venous specification and onset of AVMs by modulating Notch signalling activation.This proposal utilises an interdisciplinary approach to decipher the new targets underlying the intricate and still unknown interaction of physical and molecular mechanisms responsible for defective arterial venous specification. The results of this research will potentially provide appealing diagnostic and therapeutic opportunities for both hereditary and idiopathic AVMs.
Original text from CORDIS.
Participants
- UNIVERSITY OF LEEDS · LeedsCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union