Fig. 2.

Proposed role of HIF-1 in hypoxic pulmonary hypertension. Initially, hypoxia induces the synthesis and release of endothelin-1 (ET-1) from pulmonary endothelial and arterial smooth muscle cells (PASMCs). ET-1 binds to receptors on the PASMCs, increasing Ca²⁺ sensitivity of the contractile apparatus and upregulating HIF-1α, which induces ET-1 transcription and results in a feedforward mechanism to augment HIF activation. Downstream targets of HIF-1 include voltage-gated K⁺ channels (including Kv1.5 and Kv2.1), Na⁺/H⁺ exchanger isoform 1 (NHE1), and canonical transient receptor potential (TRPC) proteins (TRPC1 and TRPC6), which coordinate to regulate PASMC contraction, growth/survival, and migration. ppET, prepro-endothelin; [Ca²⁺]_i, intracellular Ca²⁺ concentration.