Within the pulmonary arterial tree, the NOTCH3 pathway is crucial in controlling vascular smooth muscle cell proliferation and maintaining smooth muscle cells in an undifferentiated state. Pulmonary arterial hypertension (PAH) is a fatal disease without cure, characterized by elevated pulmonary vascular resistance due to vascular smooth muscle cell proliferation in precapillary arteries, perivascular inflammation, and asymmetric neointimal hyperplasia. Here, we show that human PAH is characterized by overexpression of the NOTCH ligand JAGGED-1 (JAG-1) in small pulmonary artery smooth muscle cells and that JAG-1 selectively controls NOTCH3 signaling and cellular proliferation in an autocrine fashion. In contrast, the NOTCH ligand DELTA-LIKE 4 is minimally expressed in small pulmonary artery smooth muscle cells from individuals with PAH, inhibits NOTCH3 cleavage and signaling, and retards vascular smooth muscle cell proliferation. A new monoclonal antibody for the treatment of PAH, which blocks JAG-1 cis- and trans-induced cleavage of the NOTCH3 receptor in the pulmonary vasculature, was developed. Inhibition of JAG-1–induced NOTCH3 signaling in the lung reverses clinical and pathologic pulmonary hypertension in two rodent models of disease, without toxic side effects associated with nonspecific NOTCH inhibitors. Our data suggest opposing roles of NOTCH ligands in the pulmonary vasculature in pulmonary hypertension. We propose that selectively targeting JAG-1 activation of NOTCH3 may be an effective, safe strategy to treat PAH.
Pulmonary arterial hypertension can be reversed in rodents using a monoclonal antibody that targets the selective activation of NOTCH3 by JAGGED-1.
Vascular smooth muscle cells (vSMCs) proliferate and alter the architecture of pulmonary arteries in pulmonary arterial hypertension (PAH), contributing to elevated pulmonary vascular resistance. Here, Zhang et al. investigated the role of NOTCH3 signaling in PAH. JAGGED-1, a ligand of NOTCH3, was elevated in vSMCs from humans with PAH and mice with PH, and JAGGED-1 promoted cell proliferation in an autocrine manner. Treating mouse and rat models of PH with the anti-NOTCH3 antibody Ab 28042, which inhibits JAGGED-1–NOTCH3 signaling, reversed PH. The authors did not observe signs of local or systemic toxicity, which suggests that blocking JAGGED-1–NOTCH3 interactions could be a promising therapeutic approach for patients with PAH.