Pulmonary Fibrosis Enhances Vasodilation to Calcitonin Gene-Related Peptide
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Background
Calcitonin gene related peptide (CGRP) hyperpolarizes pulmonary arterial smooth muscle cells (SMCs) and endothelial cells (ECs) through PKA-dependent activation of K ATP channels. CGRP can diminish the severity of pulmonary fibrosis (PF), however, the effects on vascular signaling were poorly defined. We hypothesized that hyperpolarization to CGRP would be augmented in a mouse model of PF.
Methods
PF was induced in male and female C57BL/6 mice by intratracheal delivery of bleomycin (3 wk), with saline used as control (sham). Pulmonary arteries (PAs; 100-150 µm diameter) were cannulated and pressurized to 16 cmH 2 O, and endothelial tubes were studied in complementary experiments to eliminate the influence of SMCs. Membrane potential (V m ) was recorded continuously using intracellular microelectrodes. Responses were also evaluated in isolated lungs preconstricted with U46619 (∼10 mmHg).
Results
PF led to greater indices of PH in males vs. females. Isolated lungs and PAs from male PF mice had enhanced vasodilation and hyperpolarization of V m to CGRP, although no effect was observed in females. The greater vasodilation and hyperpolarization of SMCs to CGRP in males persisted in endothelium-disrupted PAs and during treatment with L-NAME indicating that ECs are not required for greater responsiveness to CGRP. With no effect on resting V m , inhibition of K ATP channels or PKA significantly attenuated hyperpolarization of SMCs and ECs, attenuated vasodilation to CGRP in PAs, and eliminated differences between groups in males. Direct activation of PKA, but not K ATP , evoked greater V m hyperpolarization and vasodilation in PF vs. sham PAs and lungs. Although no difference in sensory nerves was observed in fibrotic mice, perivascular nerve stimulation evoked greater vasodilation in PAs.
Conclusions
In a mouse model of PF, CGRP-dependent hyperpolarization of pulmonary arterial SMCs and ECs is augmented through increased PKA-dependent activation of K ATP channels leading to increased vasodilator sensitivity.
