Protein kinase C δ regulates the release of collagen type I from vascular smooth muscle cells via regulation of Cdc42

Collagen type I is the most abundant component of extracellular matrix in the arterial wall. Mice knocked out for the protein kinase C delta gene (PKC delta KO) show a marked reduction of collagen I in the arterial wall. The lack of PKC delta diminished the ability of arterial smooth muscle cells (SMCs) to secrete collagen I without significantly altering the intracellular collagen content. Moreover, the unsecreted collagen I molecules accumulate in large perinuclear puncta. These perinuclear structures colocalize with the trans-Golgi network (TGN) marker TGN38 and to a lesser degree with cis-Golgi marker (GM130) but not with early endosomal marker (EEA1). Associated with diminished collagen I secretion, PKC delta KO SMCs exhibit a significant reduction in levels of cell division cycle 42 (Cdc42) protein and mRNA. Restoring PKC delta expression partially rescues Cdc42 expression and collagen I secretion in PKC delta KO SMCs. Inhibition of Cdc42 expression or activity with small interfering RNA or secramine A in PKC delta WT SMCs eliminates collagen I secretion. Conversely, restoring Cdc42 expression in PKC delta KO SMCs enables collagen I secretion. Taken together, our data demonstrate that PKCd mediates collagen I secretion from SMCs, likely through a Cdc42-dependent mechanism.