HEMODYNAMIC ASYMMETRY IN UNILATERAL RENAL ARTERY STENOSIS REVEALED BY COMPUTATIONAL FLUID DYNAMICS ANALYSIS AND iPSC-BASED 3D ARTERY MODELS

Atherosclerosis still has substantial residual risk despite the development of effective therapies. Hemodynamic forces, particularly aberrant shear stress, are plausible drivers of lesion initiation and progression. However, their causal role has been difficult to dissect due to the lack of appropriate experimental models. We therefore focused on unilateral renal artery stenosis (RAS), a natural “internal control” condition in which atherosclerotic stenosis occurs in one renal artery while the contralateral artery remains unaffected under the same systemic milieu.

 Our objectives were twofold: (i) to identify hemodynamic factors associated with focal RAS using computed tomography (CT) angiography data analyzed by computational fluid dynamics (CFD), and (ii) to build a disease-specific, in-vitro vascular model for mechanistic testing (Fig. 1). CT angiograms underwent CFD analysis to quantify microfluidic fields. Guided by these results, bifurcating iPSC vascular models were fabricated to recapitulate stenosis-promoting hemodynamic environments.

CFD analyses were conducted using CT angiography data from 31 analyzable cases of atherosclerotic unilateral RAS, accrued at Tohoku University Hospital over the past 15 years. The aorta and renal arteries were extracted and virtually reconstructed to a healthy baseline using computer-aided design (CAD) software (Solidworks). Patient-specific flow fields were then simulated from the reconstructed 3D geometries in CFD software (COMSOL), with Doppler ultrasound–derived blood pressure and velocity serving as boundary conditions. Additional appropriate boundary conditions were applied to ensure numerical stability.

For in-vitro modeling, representative CT-derived geometries that captured salient hemodynamic features were rebuilt in CAD and used to fabricate disease-specific bifurcating vascular constructs via bioprinting of hydrogel. The human iPSC-derived endothelial cells (ECs) were cultured on the hydrogel lumen to form bifurcation artery models. To assess leukocyte–endothelium interaction, mCherry-expressing iPSC-derived monocytes were perfused through the channels, and adhesion to the EC layer was quantified.

We identified characteristic hemodynamic features associated with the stenosis side, including internal pressure (p < 0.01), maximum flow velocity (p < 0.001), wall shear velocity (p < 0.05), and vorticity (p < 0.05) (Fig.2 (a,b)). In stratified analyses, patients with dyslipidemia show more pronounced characteristics. The results may indicate that differences in flow dynamics influence the interaction of blood molecules with ECs.

By culturing iPSC–derived ECs on bio-printed hydrogel models based on CT analysis, we successfully constructed a bifurcation vascular model that preserved disease-specific shape (Fig. 2 (c)). ECs formed confluent luminal monolayers, and monocytes were perfused under defined flow. Monocyte adhesion was greater on the stenosis-mimicking branch than on the contralateral (healthy-mimicking) branch, consistent with an early atherogenic phenotype (Fig. 2 (d)).

CFD analysis revealed hemodynamic drivers of unilateral RAS, and our system successfully recapitulated key pathophysiological features. This integrated approach enables mechanistic dissection of stenosis under patient-specific flow conditions and provides a novel platform for hypothesis testing and therapy/device development.