Heterocellular Contact Can Dictate Arterial Function.

RATIONALE: Resistance arteries and conduit arteries rely upon different relative contributions of endothelial derived hyperpolarization (EDH) versus nitric oxide (NO) to achieve dilatory heterocellular signaling. Anatomically, resistance arteries use myoendothelial junctions (MEJs), endothelial cell (EC) projections that make contact with smooth muscle cells (SMCs). Conduit arteries have very few to no MEJs.

OBJECTIVE: Determine if the presence of MEJs in conduit arteries can alter heterocellular signaling.

METHODS AND RESULTS: We previously demonstrated that plasminogen activator inhibitor-1 (PAI-1) can regulate formation of MEJs. Thus, we applied pluronic gel containing PAI-1 directly to conduit arteries (carotid arteries, CAs) to determine if this could induce formation of MEJs. We found a significant increase in EC projections resembling MEJs that correlated with increased biocytin dye transfer from ECs to SMCs. Next, we used pressure myography to investigate whether these structural changes were accompanied by a functional change in vasodilatory signaling. Interestingly, PAI-1-treated CAs underwent a switch from a conduit to resistance artery vasodilatory profile via diminished NO signaling, and increased EDH signaling in response to the endothelium-dependent agonists Ach and NS309. Following PAI-1 application, we also found a significant increase in carotid expression of endothelial alpha globin, a protein predominantly expressed in resistance arteries. Carotids from mice with PAI-1, but lacking alpha globin (Hba1-/- ), demonstrated that L-NAME, an inhibitor of NO signaling, was able to prevent arterial relaxation.

CONCLUSIONS: The presence or absence of MEJs is an important determinant for influencing heterocellular communication in the arterial wall. In particular, alpha globin expression, induced within newly formed EC projections, may influence the balance between EDH and NO-mediated vasodilation.