Enhanced L-arginine-induced vasoreactivity suggests endothelial dysfunction in CADASIL.
BACKGROUND
Mutations in the Notch3 gene are the cause of CADASIL, a hereditary small vessel disease leading to stroke and vascular dementia. The disease is characterized by ultrastructural granular deposits within small arterial vessels and degeneration of vascular smooth muscle cells. Yet, little is known about endothelial function in CADASIL. Vasoreactivity induced by L-arginine, which is the substrate for endothelial nitric oxide synthase, is a parameter of endothelial function and has been shown to be altered in patients with cerebrovascular disease.


METHODS
To assess endothelial function in CADASIL, L-arginine-induced vasoreactivity was studied in 25 CADASIL subjects and 24 non-CADASIL control subjects without previous history of cerebrovascular disease by transcranial Doppler sonography of the middle cerebral artery.


RESULTS
Resting mean flow velocity was significantly reduced in patients (43.7 +/- 14.5 cm/s) compared to controls (57.0 +/- 10.4 cm/s) [p < 0.001]. Patients exhibited a significantly higher pulsatility index (PI = 0.94 +/- 0.19) than control subjects (PI = 0.79 +/- 0.11) [p < 0.01]. L-arginine-induced vasoreactivity was significantly increased in patients (36.1 +/- 15.5 % ) versus controls (27.9 +/- 8.5 %) [p < 0.05]. In patients, there was a significant reduction of the PI following L-arginine application (PI = 0.86 +/- 0.13) compared to resting PI [p < 0.01].


CONCLUSIONS
Our results may indicate a pathogenic role of impaired cerebral hemodynamics and endothelial dysfunction in CADASIL. Our finding of enhanced L-arginine vasoreactivity might have therapeutic implications for CADASIL and sporadic small vessel disease.
Peters
Nils
N
Dept. of Neurology, Klinikum Grosshadern, Ludwig-Maximilians-University, Marchioninistrasse 15, 81377, Munich, Germany. Nils.Peters@med.uni-muenchen.de
Freilinger
Tobias
T
Opherk
Christian
C
Pfefferkorn
Thomas
T
Dichgans
Martin
M
D000328:Adult; D001120:Arginine / Q000494:pharmacology*; D001783:Blood Flow Velocity / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D046589:CADASIL / Q000150:complications / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects* / Q000502:physiology; D004727:Endothelium / Q000187:drug effects* / Q000473:pathology*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D020768:Middle Cerebral Artery / Q000000981:diagnostic imaging / Q000187:drug effects; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics; D012720:Severity of Illness Index; D017585:Ultrasonography, Doppler, Transcranial / Q000379:methods; D014652:Vascular Diseases / Q000209:etiology
C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D001120:Arginine