Speaker
Description
Atherosclerotic plaques with similar luminal narrowing carry markedly different rupture risk, depending on fibrous-cap thickness, necrotic-core size, and the origin and maturity of intraplaque microvessels. We present a spatial agent-based model of a plaque-bearing arterial cross-section that couples the following mechanisms:
(i) hypoxia-driven foam-cell necrosis with variable efferocytic clearance, forming a necrotic core;
(ii) hypoxia-driven tip-cell/stalk-cell microvessel sprouting from adventitial vasa vasorum or luminal endothelium, where anastomosis confers perfusion; and
(iii) pericyte recruitment onto perfused vessels, which stabilizes the vessels and controls intraplaque hemorrhage.
(iv) A fibrous cap evolves from the balance of collagen synthesis and MMP degradation, and two-phase Glagov remodeling allows the plaque to narrow the lumen.
We calibrate cell composition and test the model's assumptions against human data: Visium spatial transcriptomics and two single-cell atlases provide healthy-versus-plaque cell proportions and show that the plaque core is uniquely hypoxic and pericyte-depleted. Simulations were used to track hypoxia, tip-cell, and pericyte-loss signatures in disease progression.
We found that efferocytosis controls necrotic-core content independently of cap thickness. Further our data suggest that pericyte coverage determines whether angiogenesis stabilizes or destabilizes a plaque and that luminal stenosis is decoupled from rupture vulnerability.
