Bone Marrow-Derived Proangiogenic Cells Mediate Pulmonary Arteriole Stiffening via Serotonin 2B Receptor Dependent Mechanism

Circ Res. 2018 Dec 7;123(12):e51-e64. doi: 10.1161/CIRCRESAHA.118.313397.

Abstract

Rationale: Pulmonary arterial hypertension is a deadly disease of the pulmonary vasculature for which no disease-modifying therapies exist. Small-vessel stiffening and remodeling are fundamental pathological features of pulmonary arterial hypertension that occur early and drive further endovascular cell dysfunction. Bone marrow (BM)-derived proangiogenic cells (PACs), a specialized heterogeneous subpopulation of myeloid lineage cells, are thought to play an important role in pathogenesis.

Objective: To determine whether BM-derived PACs directly contributed to experimental pulmonary hypertension (PH) by promoting small-vessel stiffening through 5-HT2B (serotonin 2B receptor)-mediated signaling.

Methods and results: We performed BM transplants using transgenic donor animals expressing diphtheria toxin secondary to activation of an endothelial-specific tamoxifen-inducible Cre and induced experimental PH using hypoxia with SU5416 to enhance endovascular injury and ablated BM-derived PACs, after which we measured right ventricular systolic pressures in a closed-chest procedure. BM-derived PAC lineage tracing was accomplished by transplanting BM from transgenic donor animals with fluorescently labeled hematopoietic cells and treating mice with a 5-HT2B antagonist. BM-derived PAC ablation both prevented and reversed experimental PH with SU5416-enhanced endovascular injury, reducing the number of muscularized pulmonary arterioles and normalizing arteriole stiffness as measured by atomic force microscopy. Similarly, treatment with a pharmacological antagonist of 5-HT2B also prevented experimental PH, reducing the number and stiffness of muscularized pulmonary arterioles. PACs accelerated pulmonary microvascular endothelial cell injury response in vitro, and the presence of BM-derived PACs significantly correlated with stiffer pulmonary arterioles in pulmonary arterial hypertension patients and mice with experimental PH. RNA sequencing of BM-derived PACs showed that 5-HT2B antagonism significantly altered biologic pathways regulating cell proliferation, locomotion and migration, and cytokine production and response to cytokine stimulus.

Conclusions: Together, our findings illustrate that BM-derived PACs directly contribute to experimental PH with SU5416-enhanced endovascular injury by mediating small-vessel stiffening and remodeling in a 5-HT2B signaling-dependent manner.

Keywords: bone marrow cells; cell count; hematopoietic stem cells; signal transduction; vascular remodeling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / toxicity
  • Animals
  • Arterioles / pathology
  • Cell Lineage
  • Cells, Cultured
  • Hypertension, Pulmonary / blood
  • Hypertension, Pulmonary / etiology
  • Hypertension, Pulmonary / pathology*
  • Indoles / toxicity
  • Lung / blood supply
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Progenitor Cells / cytology
  • Myeloid Progenitor Cells / metabolism*
  • Myeloid Progenitor Cells / transplantation
  • Pyrroles / toxicity
  • Receptor, Serotonin, 5-HT2B / metabolism*
  • Vascular Stiffness*

Substances

  • Angiogenesis Inhibitors
  • Indoles
  • Pyrroles
  • Receptor, Serotonin, 5-HT2B
  • Semaxinib