Elastin Regulation of Vasoreactivity in Resistance Arteries

Endothelial cells (ECs) are the primary producers of elastin in the internal elastic lamina (IEL) of resistance arteries. These arteries have distinct gaps in their IEL where ECs facilitate heterocellular communication with smooth muscle in a signaling microdomain termed the myoendothelial junction. However, the contribution of the IEL to vasodilation and blood pressure in resistance arteries is not well understood.

An endothelial-specific elastin knockout mouse (EC-specific Eln^fl/fl/Cre⁺) was used to alter the IEL and myoendothelial junctions. Myoendothelial junction resident proteins were localized by en face, pressure myography assessed the effect of elastin depletion on vessel dilation, and blood pressure was measured using radiotelemetry.

Using single-cell RNA-sequencing, we found Eln mRNA enriched in arterial endothelium. In EC-specific Eln^fl/fl/Cre⁺ mice, the localization of the myoendothelial junction resident protein Hbα (α hemoglobin) becomes diffuse and disorganized. Normally, Hbα regulates eNOS (endothelial nitric oxide synthase) by sequestering NO, promoting endothelial-derived hyperpolarization as the predominant vasodilation mechanism. However, in EC-specific Eln^fl/fl/Cre⁺ mice, Hbα expression and interaction with eNOS are significantly reduced, corresponding to increased NO signaling via acetylcholine dilation. Intact arteries also exhibit decreased smooth muscle contractility with the diminished IEL. These vascular deficiencies suggested a hypotensive phenotype, but EC-specific Eln^fl/fl/Cre⁺ mice's blood pressure was not different from controls.

Our findings suggest that elastin deficiency in resistance arteries alters their vasoreactive properties, resulting in poor contraction and dilation. Furthermore, the absence of the holes in the IEL mislocalizes Hbα and eNOS in resistance arteries, switching the vasodilatory mechanism from endothelial-derived hyperpolarization to NO signaling, mimicking larger conduit arteries.