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Abstract

Abnormalities of tracheal smooth muscle (SM) formation are associated
with several clinical disorders including tracheal stenosis and
tracheomalacia. However, the cellular and molecular mechanisms
underlying tracheal SM formation remain poorly understood. Here, it is
shown that the T-type calcium channel CACNA1H is a novel regulator of
tracheal SM formation and contraction. Cacna1h in an ethylnitrosourea
forward genetic screen for regulators of respiratory disease using the
mouse as a model is identified. Cacna1h mutants exhibit tracheal
stenosis, disorganized SM and compromised tracheal contraction. CACNA1H
is essential to maintain actin polymerization, which is required for
tracheal SM organization and tube formation. This process appears to be
partially mediated through activation of the actin regulator RhoA, as
pharmacological increase of RhoA activity ameliorates the Cacna1h-mutant
trachea phenotypes. Analysis of human tracheal tissues indicates that a
decrease in CACNA1H protein levels is associated with congenital
tracheostenosis. These results provide insight into the role for the
T-type calcium channel in cytoskeletal organization and SM formation
during tracheal tube formation and suggest novel targets for congenital
tracheostenosis intervention.
Defects in the T-type calcium channel CACNA1H cause defects in airway
smooth muscle formation and its cytoskeletal organization in tracheal
stenosis, and pharmacological increase of RhoA activity can partially
attenuate these defects in mice. Analysis of human tracheal tissues
suggests that a decrease in CACNA1H proteins is associated with tracheal
stenosis in patients. image