Macrophages are part of cause, not consequence, in PAH

Abstract

BackgroundAlthough pulmonary arterial hypertension (PAH) is a progressive cardiopulmonary disease, increasing evidence suggests that inflammatory cells play an equally important role in progression of this disease. PAH can thus be thought of as a failure to effectively resolve pulmonary vascular injury. Because PAH is mostly associated with mutations in the bone morphogenic protein receptor 2 (BMPR2) or suppression of BMP pathway we sought test the hypothesis that BMPR2 mutant macrophages contribute to achieving a sustaining pulmonary vascular injury causing right ventricular dysfunction.MethodsWe used two mouse models: 1] the Rosa26‐rtTA2 3 X TetO7‐Bmpr2delx4 FVB/N mice (BMPR2 mutant mouse), in which mutant Bmpr2 is universally expressed; and 2] the LysM‐Cre X floxed BMPR2 X floxed eGFP monocyte lineage‐specific BMPR2 knockout mouse model (macrophage specific BMPR2 KO mouse), in which Bmpr2 expression is completely knockdown in cells of monocytic lineage. The BMPR2 mutant mice were given weekly liposomal clodronate injections for 4 weeks to eliminate macrophages. The macrophage specific BMPR2 KO mice underwent sugen‐hypoxia treatment for 3 weeks to cause pulmonary vascular injury.ResultsIn the BMPR2 mutant mice, following transgene activation for 6 weeks there was significant increase (p<0.05) in right ventricular systolic pressure (RVSP) as compared to control mice. However, elimination of macrophages using clodronate normalized RVSP in BMPR2 mutant mice (p<0.05) suggesting that macrophages are required for development of BMPR2 related PAH in animal model of PAH with mutant Bmpr2. In the untreated macrophage specific BMPR2 KO mouse the RVSP were moderately increased compared to the control littermates. With sugen hypoxia treatment there was a significant increase in RVSP in both control and macrophage specific BMPR2 KO mouse. However, in the macrophage specific BMPR2 KO mouse there was significant increase in RVSP compared to control littermates. Further, in sugen‐hypoxia treated macrophage specific BMPR2 KO mouse lung, by immunofluorescence, we were able to demonstrate incorporation of macrophages in walls of pulmonary vessels suggesting that BMPR2 KO macrophages play a role in vascular remodeling of pulmonary vessels in animal model of PAH as a result of vascular injury.ConclusionOur results indicate that mutant BMPR2 macrophages are important in progression of disease in animal models PAH and suggest that macrophages are central in failure to resolve ongoing pulmonary vascular injury. Further studies are warranted to understand the mechanism behind failure to resolve vascular injury, which will be central to develop novel therapeutic interventions.Support or Funding Information2R01HL95797