(LINE DENOTES CHANGES FROM A1) Pulmonary arterial hypertension (PAH) has been linked to reduced expression of bone morphogenetic protein receptor II (BMPRII). This proposal addresses our novel and potentially ground breaking findings that impaired BMPRII signaling can lead to abnormal synthesis and assembly of elastin fibers in the walls of pulmonary arteries (PA). Structural abnormalities in elastin assembly increase stiffness of the PAs, augmenting right ventricular work. They also result in the susceptibility of elastin fibers to degradation. If this occurs in response to proteolytic activity, the consequent release of elastin peptides and elastin fiber-bound growth factors can create a pro-proliferative and pro-inflammatory milieu in the PA wall. These features are associated with progressive PAH. In our Preliminary Studies we show, for the first time, that BMPRII ligands, in particular BMP4, can increase mRNA and protein levels of tropoelastin, the soluble precursor of elastin, in cultured human (h) PA SMC. We show that this results in the assembly of dense elastin. In contrast, while TGFss1 stimulates more tropoelastin production than BMP4, the elastin fibers are less well assembled, a feature described in PAs of animal models and patients with PAH. We attribute this difference to our observation that TGFss1 reduces Jagged1, a molecule judged necessary to organize elastin into a lamellar structure by its interaction with microfibrillar associated glycoprotein 2. To support our observations in cultured cells we have shown, that mice with deletion of BMPRII in SMC produce elastin lamellae that are more susceptible to degradation when compared to littermate controls. We also show that mice with compound heterozygosity for BMPRII and BMPRIA have more severe hypoxia-induced PAH when compared to single heterozygotes as judged by both heightened muscularity and loss of peripheral (P) PAs, features that we attribute to enhanced TGF? receptor signaling.
Our first aim i n this proposal is to use hPA SMC from elastic (EPA) and PPAs to determine how BMPs via BMPRII and IA transduce signals that stimulate tropoelastin synthesis and to establish how Jagged1 regulates elastin assembly. As part of this aim, we will determine whether the mechanism accounting for inability of EPA and PPA SMC from patients with advanced PAH to synthesize and repair tropoelastin is related to stabilization of transforming growth interacting factor (TGIF), a pSmad co- repressor.
Our second aim i s to determine whether, in mice with deletion of BMPRII in SMCs or with compound heterozygosity for BMPRII and either BMPRIA or BMP4, there is increased activation of the TGFss signaling pathway, and impaired neosynthesis and assembly of elastin. We will determine whether this enhances elastin susceptibility to degradation, is associated with increased PA stiffness, and with the propensity to develop elevated PA resistance and morphologic features of PAH, including the induction of a pro-proliferative and pro-inflammatory state in the PA wall. Our studies could lead to using elastin degradation products as biomarkers of early and progressive PAH, and to new treatments that stabilize the elastin matrix.
New information has emerged from our studies supported during the current grant period that link abnormalities in bone morphogenetic protein receptor (BMPR)II in patients with pulmonary arterial (PA) hypertension (PAH), with a propensity to produce poorly assembled elastin fibers that are susceptible to degradation: these features contribute to vessel loss, occlusion and inflammation, hallmarks of PAH. We plan to discover how elastin production and assembly are dysregulated when there is a loss of function of BMPRII or a gain of function of TGFss1, by studying PA smooth muscle cells in culture from normal and PAH patients and by analyzing abnormalities in PA elastin in genetically modified mice, that we will relate to PA stiffness, and to proliferation and inflammation in the PA walls. These studies could produce new biomarkers of risk and progression of PAH related to elastin degradation, and may indicate that stabilizing elastin would be effective therapeutically in preventing or reversing PAH.
|Zamanian, Roham T; Hedlin, Haley; Greuenwald, Paul et al. (2018) Features and Outcomes of Methamphetamine-associated Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 197:788-800|
|Miyagawa, Kazuya; Shi, Minyi; Chen, Pin-I et al. (2018) Smooth Muscle Contact Drives Endothelial Regeneration by BMPR2-Notch1 Mediated Metabolic and Epigenetic Changes. Circ Res :|
|Tojais, Nancy F; Cao, Aiqin; Lai, Ying-Ju et al. (2017) Codependence of Bone Morphogenetic Protein Receptor 2 and Transforming Growth Factor-? in Elastic Fiber Assembly and Its Perturbation in Pulmonary Arterial Hypertension. Arterioscler Thromb Vasc Biol 37:1559-1569|
|Bonnet, Sébastien; Provencher, Steeve; Guignabert, Christophe et al. (2017) Translating Research into Improved Patient Care in Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 195:583-595|
|Newman, John H; Rich, Stuart; Abman, Steven H et al. (2017) Enhancing Insights into Pulmonary Vascular Disease through a Precision Medicine Approach. A Joint NHLBI-Cardiovascular Medical Research and Education Fund Workshop Report. Am J Respir Crit Care Med 195:1661-1670|
|Chen, Pin-I; Cao, Aiqin; Miyagawa, Kazuya et al. (2017) Amphetamines promote mitochondrial dysfunction and DNA damage in pulmonary hypertension. JCI Insight 2:e90427|
|Rabinovitch, Marlene (2016) NETs Activate Pulmonary Arterial Endothelial Cells. Arterioscler Thromb Vasc Biol 36:2035-7|
|Hopper, Rachel K; Moonen, Jan-Renier A J; Diebold, Isabel et al. (2016) In Pulmonary Arterial Hypertension, Reduced BMPR2 Promotes Endothelial-to-Mesenchymal Transition via HMGA1 and Its Target Slug. Circulation 133:1783-94|
|Amsallem, Myriam; Kuznetsova, Tatiana; Hanneman, Kate et al. (2016) Right heart imaging in patients with heart failure: a tale of two ventricles. Curr Opin Cardiol 31:469-82|
|Vattulainen-Collanus, Sanna; Akinrinade, Oyediran; Li, Molong et al. (2016) Loss of PPAR? in endothelial cells leads to impaired angiogenesis. J Cell Sci 129:693-705|
Showing the most recent 10 out of 39 publications