Figure 2.

Schematic representation of the role of nSMase-derived ceramide in hypoxic pulmonary vasoconstriction (HPV). Hypoxia promotes mitochondria-derived ROS, which in turn stimulates the production of ceramide from nSMase. Ceramide amplifies ROS production through a PKCζ-dependent activation of NADPH oxidase. ROS inhibit Kv channels leading to membrane depolarization and activation of L-type Ca²⁺ channels, and activate RhoK-mediated Ca²⁺-sensitization. In addition, ceramide via CFTR stimulates Ca²⁺ entry through TRPC6 and, via a concomitant activation of SK1, leads to S1P generation which contributes to the contraction though the activation of RhoK. Black lines indicate a stimulatory effect, whereas the red line indicates an inhibitory effect. CFTR: cystic fibrosis transmembrane conductance regulator; Kv: voltage-gated K⁺ channels; nSMase: neutral sphingomyelinase; PKCζ: protein kinase Cζ; RhoK: Rho-kinase; ROS: reactive oxygen species; S1P: sphingosine-1-phosophate; S1PR: sphingosine-1-phosophate receptor; SK1: sphingosine kinase 1; VSMC: vascular smooth muscle cell. Black arrows indicate activation and red arrow indicates inhibition.