Abstract
When a large artery becomes occluded, hemodynamic changes stimulate remodeling of arterial networks to form collateral arteries in a process termed arteriogenesis. However, the structural changes necessary for collateral remodeling have not been defined. We hypothesize that deconstruction of the extracellular matrix is essential to remodel smaller arteries into effective collaterals. Using multiphoton microscopy, we analyzed collagen and elastin structure in maturing collateral arteries isolated from ischemic rat hindlimbs. Collateral arteries harvested at different timepoints showed progressive diameter expansion associated with striking rearrangement of internal elastic lamina (IEL) into a loose fibrous mesh, a pattern persisting at 8 weeks. Despite a 2.5-fold increase in luminal diameter, total elastin content remained unchanged in collaterals compared with control arteries. Among the collateral midzones, baseline elastic fiber content was low. Outward remodeling of these vessels with a 10–20 fold diameter increase was associated with fractures of the elastic fibers and evidence of increased wall tension, as demonstrated by the straightening of the adventitial collagen. Inhibition of lysyl oxidase (LOX) function with β-aminopropionitrile resulted in severe fragmentation or complete loss of continuity of the IEL in developing collaterals. Collateral artery development is associated with permanent redistribution of existing elastic fibers to accommodate diameter growth. We found no evidence of new elastic fiber formation. Stabilization of the arterial wall during outward remodeling is necessary and dependent on LOX activity.
Highlights
Collateral artery growth is a spontaneous, life- and limb-preserving response to arterial occlusive disease (AOD) that maintains end-organ perfusion when a larger conductance artery becomes occluded
Given the observations of elastin degradation occurring in early collateral remodeling along with the necessity of maintaining internal elastic lamina (IEL) elastic fiber integrity since loss of continuity appears irreversible, we examined the role of lysyl oxidase (LOX) during arteriogenesis
While we did not observe an increase in elastic fiber content or elastic tissue mass to coincide with vessel diameter increase, it appears that cross-linking of new elastin is of critical importance since inhibition of LOX resulted in rapid fragmentation and total loss of continuity of the remodeling IEL
Summary
Collateral artery growth is a spontaneous, life- and limb-preserving response to arterial occlusive disease (AOD) that maintains end-organ perfusion when a larger conductance artery becomes occluded. With obstruction of a conductance artery (as occurs in peripheral arterial disease), flow pattern changes initially elicit vasodilation in these small vessels. When flow changes are sustained, inflammatory cell recruitment and structural expansion occurs. These transformed vessels become clinically important conduits that maintain target tissue perfusion [3]. This process has been termed “arteriogenesis” and has greater capacity for restoring tissue perfusion than angiogenesis or vasculogenesis, under such circumstances [4,5]
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