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Updated: Nov 14, 2025
Assessing Murine Resistance Artery Function Using Pressure Myography
Published on: June 7, 2013
Peripheral arteriopathy caused by Notch3 gain-of-function mutation involves ER and oxidative stress and blunting of
Karla B Neves1, Hannah E Morris1, Rhéure Alves-Lopes1
1Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, U.K.
Insights
Notch3 mutations in CADASIL cause peripheral vascular dysfunction through altered calcium handling, oxidative stress, and impaired signaling. Treatments targeting Rho kinase and ER stress show promise for these vascular issues.
Area of Science:
- Vascular Biology
- Neurodegenerative Diseases
- Genetics
Background:
- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is caused by Notch3 mutations, leading to stroke and dementia.
- CADASIL is characterized by vascular dysfunction and granular osmiophilic material (GOM) in cerebral small vessels, with potential systemic vessel impact.
- Mechanisms of peripheral vasculopathy in CADASIL remain incompletely understood.
Purpose of the Study:
- To investigate the mechanisms underlying peripheral vasculopathy in CADASIL caused by Notch3 gain-of-function mutations.
- To analyze vascular characteristics and pathophysiological processes in systemic vessels affected by CADASIL.
- To identify novel pathways involved in peripheral arteriopathy induced by Notch3 mutations.
Main Methods:
- Studied small arteries and vascular smooth muscle cells (VSMCs) from TgNotch3R169C mice (CADASIL model).
- Analyzed VSMCs from peripheral arteries of CADASIL patients and post-mortem brains from CADASIL individuals.
- Assessed vasoreactivity, vasorelaxation, calcium transients, signaling pathways (Rho kinase, eNOS/sGC/cGMP), and endoplasmic reticulum (ER) stress.
Main Results:
- TgNotch3R169C vessels showed GOM deposits, increased vasoreactivity, and impaired vasorelaxation, responsive to fasudil and 4-PBA.
- CADASIL VSMCs exhibited increased Ca2+ transients, Ca2+ channel expression, Rho GEFs, and ER stress proteins.
- Impaired vasorelaxation involved decreased eNOS phosphorylation, reduced cGMP, increased sGC oxidation, and decreased H2O2; these were observed in patient VSMCs and normalized by fasudil and 4-PBA.
Conclusions:
- Peripheral vascular dysfunction in CADASIL is linked to altered Ca2+ homeostasis, oxidative stress, and blunted eNOS/sGC/cGMP signaling.
- Rho kinase and ER stress pathways are implicated in the vascular dysfunction observed in CADASIL.
- Novel pathways contributing to peripheral arteriopathy in Notch3-mutated CADASIL have been identified, potentially relevant to cerebral vessels as well.
Abstract:
Notch3 mutations cause Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), which predisposes to stroke and dementia. CADASIL is characterised by vascular dysfunction and granular osmiophilic material (GOM) accumulation in cerebral small vessels. Systemic vessels may also be impacted by Notch3 mutations. However vascular characteristics and pathophysiological processes remain elusive. We investigated mechanisms underlying the peripheral vasculopathy mediated by CADASIL-causing Notch3 gain-of-function mutation. We studied: (i) small arteries and vascular smooth muscle cells (VSMCs) from TgNotch3R169C mice (CADASIL model), (ii) VSMCs from peripheral arteries from CADASIL patients, and (iii) post-mortem brains from CADASIL individuals. TgNotch3R169C vessels exhibited GOM deposits, increased vasoreactivity and impaired vasorelaxation. Hypercontractile responses were normalised by fasudil (Rho kinase inhibitor) and 4-phenylbutyrate (4-PBA; endoplasmic-reticulum (ER) stress inhibitor). Ca2+ transients and Ca2+ channel expression were increased in CADASIL VSMCs, with increased expression of Rho guanine nucleotide-exchange factors (GEFs) and ER stress proteins. Vasorelaxation mechanisms were impaired in CADASIL, evidenced by decreased endothelial nitric oxide synthase (eNOS) phosphorylation and reduced cyclic guanosine 3',5'-monophosphate (cGMP) levels, with associated increased soluble guanylate cyclase (sGC) oxidation, decreased sGC activity and reduced levels of the vasodilator hydrogen peroxide (H2O2). In VSMCs from CADASIL patients, sGC oxidation was increased and cGMP levels decreased, effects normalised by fasudil and 4-PBA. Cerebral vessels in CADASIL patients exhibited significant oxidative damage. In conclusion, peripheral vascular dysfunction in CADASIL is associated with altered Ca2+ homoeostasis, oxidative stress and blunted eNOS/sGC/cGMP signaling, processes involving Rho kinase and ER stress. We identify novel pathways underlying the peripheral arteriopathy induced by Notch3 gain-of-function mutation, phenomena that may also be important in cerebral vessels.
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