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Dilated cardiomyopathy (DCM) is a major cause of mortality and morbidity in cardiac patients. Aging is often an ignored etiology of pathological conditions. Quantification of DCM and aging associated cardiac structural remodeling is important in guiding and evaluating therapeutic interventions. Diffusion tensor magnetic resonance imaging (DTMRI) has recently been used for nondestructive characterization of three-dimensional myofiber structure. In this study, we explored the potential of DTMRI in delineating microscopic structural remodeling in aging and DCM hearts. Six month (n = 10) and nine month old (n = 11) DCM (TO-2) hamsters and their age-matched controls (F1β) were characterized. Both aging and DCM hearts showed increased diffusivity and decreased diffusion anisotropy. DTMRI images of DCM hearts also revealed a subgroup of imaging pixels characterized by decreased radial diffusivity and increased FA. The location of these pixels showed qualitative agreement with regions of calcium deposition determined by X-ray CT imaging. Histological analysis confirmed expanded extracellular space in aging and DCM hearts as well as substantial calcium deposition in DCM hearts. These results suggest that DTMRI may provide a noninvasive technique to delineate structural remodeling associated with aging and DCM progression at the tissue and cellular level without the use of an exogenous contrast agent.

The circle of Willis (cW) is a major arterial collateral structure interconnecting hemispheric circulation within the brain, and in humans, anatomical variation of the cW is linked to stroke risk. Our prior studies in adult mice deficient in vascular smooth muscle cell (vSMC) Notch signaling revealed altered cerebroarterial maturation and patterning, including an anatomically incompetent cW similar to human variants. However, a developmental dependency on Notch signaling for cW formation in this model remained uncharacterized. Through temporospatial embryonic analyses, we now demonstrate that cW assembly is a pre-natal process highly sensitive to vSMC Notch signals, whose absence results in delayed nascent vascular plexus formation and under-development of the cW including the key anterior communicating artery (AComA) interconnecting anterior forebrain circulation. Mutant embryos additionally feature reduced vSMC coverage, non-uniform calibers and asymmetric branching at bifurcations of the major proximal cerebral arteries. At the cellular level, a notable reduction in vascular endothelial cell proliferation exists in the region of AComA assembly despite the presence of Vegfa. Furthermore, Notch signaling-deficient vSMCs in developing cerebral vessels feature reduced Pdgfrβ and Jagged1 levels and impaired proliferation. These collective findings in the embryonic brain support studies in adult animals demonstrating a reliance on intact vSMC Notch signaling for optimal neovascular responses to angiogenic stimuli. Importantly, the new data provide unique insights into the native formation of the cW and underscore a pioneering developmental role for vSMC Notch signaling in regulating temporospatial assembly of the clinically relevant cW.

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