| First Author | Calvier L | Year | 2019 |
| Journal | Circ Res | Volume | 124 |
| Issue | 12 | Pages | 1778-1785 |
| PubMed ID | 31023188 | Mgi Jnum | J:289252 |
| Mgi Id | MGI:6434720 | Doi | 10.1161/CIRCRESAHA.119.315088 |
| Citation | Calvier L, et al. (2019) LRP1 Deficiency in Vascular SMC Leads to Pulmonary Arterial Hypertension That Is Reversed by PPARgamma Activation. Circ Res 124(12):1778-1785 |
| abstractText | RATIONALE: Arterial remodeling-a hallmark of many cardiovascular pathologies including pulmonary arterial hypertension (PAH)-is regulated by TGFbeta1 (transforming growth factor-beta1)-TGFbeta receptors and the antagonistic, vasoprotective BMPR2 (bone morphogenetic protein receptor 2)-PPARgamma (peroxisome proliferator-activated receptor-gamma) axis. However, it is unclear which factors drive detrimental TGFbeta1 pathways in the hypertensive pulmonary vasculature. OBJECTIVE: We hypothesized that LRP1 (low-density lipoprotein receptor-related protein 1) expression is decreased in PAH, leading to enhancement (disinhibition) of TGFbeta1 signals and that the PPARgamma agonist pioglitazone can restore vascular homeostasis and prevent PAH resulting from LRP1 deletion in vascular smooth muscle cells (SMCs). METHODS AND RESULTS: Targeted deletion of LRP1 in vascular SMC (smLRP1(-/-)) in mice disinhibited TGFbeta1-CTGF (connective tissue growth factor) signaling, leading to spontaneous PAH and distal pulmonary arterial muscularization as assessed by closed-chest cardiac catheterization and anti-alphaSMA staining. Pioglitazone inhibited the canonical TGFbeta1-CTGF axis in human pulmonary artery SMC and smLRP1(-/-) main pulmonary artery (CTGF and NOX4) and reversed PAH in smLRP1(-/-) mice. TGFbeta1 boosted pSmad3 in PASMC from smLRP1(-/-) mice versus controls. Pioglitazone-activated PPARgamma binds to Smad3 in human pulmonary artery SMC (coimmunoprecipitation), thereby blocking its phosphorylation and overriding LRP1 deficiency. Finally, mRNA and protein expression of LRP1 was decreased in pulmonary plexiform lesions of patients with end-stage idiopathic PAH (laser capture microdissection, qPCR, and immunohistochemistry). Downregulation of LRP1 protein was also demonstrated in explanted PASMC from patients with PAH and accompanied by enhanced TGFbeta1-pSmad3-CTGF signaling and increased TGFbeta1-induced PASMC proliferation that was prevented by pioglitazone. CONCLUSIONS: Here, we identify LRP1 as an integrator of TGFbeta1-mediated mechanisms that regulate vascular remodeling in mice and clinical PAH and PPARgamma as a therapeutic target that controls canonical TGFbeta1 pathways. Hence, pharmacologic PPARgamma activation represents a promising new therapy for patients with PAH who lack the vasoprotective LRP1 in vascular SMC. |
