Leducq Center Against Small Vessel Disease

From monogenic to common SVD

Hypertension and age likely contribute to common SVD^13,23. Hypertension produces endothelial and vascular muscle dysfunction; altered microvascular pressure regulation; structural changes, including an inward vascular remodeling that limits vasodilator responses; and increased susceptibility to ischemic injury^9,16. Genome-wide association studies (GWAS) have provided little insight into the genes that contribute to SVD¹¹. Our hypothesis, supported by the recent finding that common variants of the NOTCH3 gene increase the risk of age-related white matter lesions in hypertensive patients²⁴, is that the risk for sporadic SVD is affected by variants of genes that contribute to CADASIL or CARASIL pathogenesis, potentially including genes encoding GOM constituents, Notch3^ICD targets or HtrA1 substrates, as well as NOTCH3 and HTRA1. Thus, the molecular changes and resulting small vessel pathology that arise in CADASIL/CARASIL as a consequence of a single point mutation in NOTCH3/HTRA1 may be produced in common SVD by a combination of factors, including aging, hypertension and altered expression/function of specific variants of disease-contributing genes. Members of this Network will explore the contribution of these candidate genes by combining functional studies in mice (Faraci, Joutel, Nelson) and genetic studies in humans (Chabriat, Tzourio, Dichgans).

Angiotensin II (Ang II) is a major therapeutic target in hypertension and plays a central role in promoting vascular disease in the presence of other vascular risk factors, including aging. To address these aspects in the context of SVD in the mouse, we plan to use Ang II-dependent models of vascular disease and hypertension starting with inducible mouse models of activation and abrogation of Notch3 activity in SMCs. The following major properties will be examined: myogenic tone in isolated arterioles (Nelson), arterial and microvascular pressure, regulation of vascular tone and inward remodeling of the cerebral microcirculation, brain capillary density and brain parenchyma integrity (Faraci, Joutel).

For studies in humans, the first year plan will focus on launching the recruitment of a cohort of at least 200 extensively phenotyped, symptomatic SVD patients from the participating neurological departments, taking advantage of existing databases. We will apply stringent inclusion criteria, namely <75 years old, presence of at least one lacunar infarct on MRI, extensive white matter hyperintensity volume (WMHV), confirmation of a non- cardioaortic source of cerebral embolism, absence of severe large-artery disease, and absence of non-lacunar infarcts on MRI (Chabriat).