Genotype-specific alterations in vascular smooth muscle cell function in cystic fibrosis piglets

BackgroundThe most common CF-causing mutations interfere with CFTR trafficking from the endoplasmic reticulum (CFTR-F508del) or prematurely terminate transcription (CFTR-null). We suspected that genotype-specific patterns of CFTR expression would have differential effects on smooth muscle cell calcium signaling and hence vascular tone. We hypothesized that compared to wild-type or CFTR-null aorta, aorta from CFTR-F508del (dF) piglets will have reduced endoplasmic reticulum calcium mobilization and decreased vasoconstriction.MethodsAortic reactivity was assessed by myography, and ratiometric calcium imaging was performed in isolated vascular smooth muscle cells.ResultsAorta from dF piglets had reduced myogenic tone (P < 0.001) and decreased constriction to KCl (P < 0.05). Combined inhibition of ryanodine and IP3 receptors decreased wild-type and CFTR-null responses to levels seen in dF aorta. Compared to wild-type cells, dF-expressing smooth muscle cells had reduced calcium transients, while CFTR-null cells had decreased baseline intracellular calcium concentrations.ConclusionsExpression of CFTR-F508del interferes with smooth muscle cell calcium handling and decreases aortic responsiveness.