2025/01/01 by Paolo Madeddu, Styliani Goulopoulou, David Wambeke · 1 voice
Medicine · #Coagulation, Bradykinin, Polyphosphates, and Angioedema #Nitric Oxide and Endothelin Effects #Renin-Angiotensin System Studies
paper · doi:10.1530/vb-25-0006
openalex publication_date 2025/01/01 · openalex created_date 2025/11/07 · openalex updated_date 2026/07/21
Abstract: Endothelial cells regulate vascular tone by releasing nitric oxide (NO) and prostacyclin (PGI2), as well as by initiating hyperpolarization of vascular smooth muscle cells through K+ channels and myoendothelial coupling. This review highlights the therapeutic potential of targeting endothelium-dependent hyperpolarization (EDH) to address unmet needs in microvascular disorders such as cerebral small vessel disease, an important cause of stroke and dementia, and preeclampsia, a major pregnancy complication associated with maternal and fetal morbidity. Oxidative stress, connexin dysfunction, and impaired K+ channel signaling disrupt electrical coupling between endothelium and smooth muscle cells, leading to loss of vascular homeostasis. Building on this mechanistic convergence, we propose a multimodal therapeutic strategy to restore EDH in concert with the NO and PGI2 pathways. Within this framework, human tissue kallikrein-1 (KLK1) exemplifies an integrated therapeutic approach by simultaneously engaging multiple endothelial vasodilator mechanisms. Through bradykinin B2 receptor signaling, KLK1 enhances NO and PGI2 production while also promoting EDH via K+ channel activation. Its recombinant form, rinvecalinase alfa (DM199), has demonstrated consistent benefit in early-phase clinical trials, supporting its potential to restore endothelial balance. By reactivating these complementary vasodilatory pathways, DM199 improves microvascular perfusion and endothelial resilience, positioning it as a prototype multimodal therapy for microvascular diseases. Key message: Restoring endothelium-derived hyperpolarization alongside NO and prostacyclin signaling represents a promising multimodal approach to treat endothelial dysfunction and microvascular disorders.