Bmp signaling in pulmonary vascular homeostasis and disease

Abstract

Bone morphogenetic protein (Bmp) signaling is critical for vascular development and homeostasis. Defects in this pathway lead to multiple vascular diseases, including Heritable Pulmonary Arterial Hypertension (HPAH), which is genetically linked to mutations in Bone Morphogenetic Protein Receptor Type 2 (BMPR2). All forms of PAH display structural remodeling of resistance-level pulmonary arteries, suggesting that defective Bmp signaling might underlie other forms of PAH, even in the absence of BMPR2 mutations. Therefore, we utilized a genetics-based approach in mice to examine the functional role of Bmp signaling in hypoxia-induced pulmonary hypertension (PH). Chapters 2 and 3 describe work that is now published. These studies illustrate that both Bmpr2 and Bmp2 (Bmp2+/-) mutant mice have defective regulation of pulmonary endothelial nitric oxide synthase (eNOS), indicating that Bmp signaling directly regulates pulmonary vascular tone. In contrast to Bmp2+/- mice, Bmp4 deficient (Bmp4LacZ/+) mice have preserved regulation of eNOS. Moreover, Bmp2+/- mice develop increased hypoxia-induced vascular remodeling and PH, while previous work showed that Bmp4LacZ/+ mice are partially protected from these effects. These studies indicate that Bmp2 and Bmp4 oppositely affect the development of hypoxic PH, and that regulation of eNOS is likely a key protective effect mediated by Bmp2 and Bmpr2 in the pulmonary vasculature. The work shown in Chapter 4, which has been submitted for publication, explores the role of Id1 as a downstream mediator of Bmp4-dependent responses in the pulmonary vasculature. A previous study showed that Bmp4LacZ/+ mice display impaired hypoxia-induced vascular smooth muscle cell (VSMC) proliferation with decreased Id1 expression, suggesting that Id1 might promote VSMC proliferation in hypoxia. However, using Id1 null mice, we show that Id1 expression is not required for hypoxic-induced VSMC proliferation or PH. This finding might be due to functional compensation, since expression of the closely-related Id3 is selectively up-regulated in Id1 null peripheral vessel VSMC. Collectively, these studies provide functional insight into Bmp signaling in pulmonary vascular homeostasis. They add to an understanding of human PAH by illustrating distinct downstream events associated with Bmp2- vs. Bmp4-signaling in vivo. Additionally, they provide potential targets for future therapies.