TY - JOUR
T1 - Pneumonectomy combined with SU5416 or monocrotaline pyrrole does not cause severe pulmonary hypertension in mice
AU - Sun, Xiao-Qing
AU - Klouda, Timothy
AU - Barnasconi, Suzanne
AU - Schalij, Ingrid
AU - Schwab, Janne
AU - Nielsen-Kudsk, Anders Hammer
AU - Axelsen, Julie Sørensen
AU - Andersen, Asger
AU - Aman, Jurjan
AU - de Man, Frances S
AU - Bogaard, Harm Jan
AU - Yuan, Ke
AU - Yoshida, Keimei
PY - 2024/8/1
Y1 - 2024/8/1
N2 - In the field of pulmonary hypertension (PH), a well-established protocol to induce severe angioproliferation in rats (SuHx) involves combining the VEGF-R inhibitor Sugen 5416 (SU5416) with 3 wk of hypoxia (Hx). In addition, injecting monocrotaline (MCT) into rats can induce inflammation and shear stress in the pulmonary vasculature, leading to neointima-like remodeling. However, the SuHx protocol in mice is still controversial, with some studies suggesting it yields higher and reversible PH than Hx alone, possibly due to species-dependent hypoxic responses. To establish an alternative rodent model of PH, we hypothesized mice would be more sensitive to hemodynamic changes secondary to shear stress compared with Hx. We attempted to induce severe and irreversible PH in mice by combining SU5416 or monocrotaline pyrrole (MCTP) injection with pneumonectomy (PNx). However, our experiments showed SU5416 administered to mice at various time points after PNx did not result in severe PH. Similarly, mice injected with MCTP after PNx (MPNx) showed no difference in right ventricular systolic pressure or exacerbated pulmonary vascular remodeling compared with PNx alone. These findings collectively demonstrate that C57/B6 mice do not develop severe and persistent PH when PNx is combined with either SU5416 or MCTP.
NEW & NOTEWORTHY We attempted to establish a mouse model of severe and irreversible pulmonary hypertension by substituting hypoxia with pulmonary overcirculation. To do so, we treated mice with either SU5416 or monocrotaline pyrrole after pneumonectomy and performed hemodynamic evaluations for PH. Despite this "two-hit" protocol, mice did not exhibit signs of severe pulmonary hypertension or exacerbated pulmonary vascular remodeling compared with PNx alone.
AB - In the field of pulmonary hypertension (PH), a well-established protocol to induce severe angioproliferation in rats (SuHx) involves combining the VEGF-R inhibitor Sugen 5416 (SU5416) with 3 wk of hypoxia (Hx). In addition, injecting monocrotaline (MCT) into rats can induce inflammation and shear stress in the pulmonary vasculature, leading to neointima-like remodeling. However, the SuHx protocol in mice is still controversial, with some studies suggesting it yields higher and reversible PH than Hx alone, possibly due to species-dependent hypoxic responses. To establish an alternative rodent model of PH, we hypothesized mice would be more sensitive to hemodynamic changes secondary to shear stress compared with Hx. We attempted to induce severe and irreversible PH in mice by combining SU5416 or monocrotaline pyrrole (MCTP) injection with pneumonectomy (PNx). However, our experiments showed SU5416 administered to mice at various time points after PNx did not result in severe PH. Similarly, mice injected with MCTP after PNx (MPNx) showed no difference in right ventricular systolic pressure or exacerbated pulmonary vascular remodeling compared with PNx alone. These findings collectively demonstrate that C57/B6 mice do not develop severe and persistent PH when PNx is combined with either SU5416 or MCTP.
NEW & NOTEWORTHY We attempted to establish a mouse model of severe and irreversible pulmonary hypertension by substituting hypoxia with pulmonary overcirculation. To do so, we treated mice with either SU5416 or monocrotaline pyrrole after pneumonectomy and performed hemodynamic evaluations for PH. Despite this "two-hit" protocol, mice did not exhibit signs of severe pulmonary hypertension or exacerbated pulmonary vascular remodeling compared with PNx alone.
KW - Animals
KW - Disease Models, Animal
KW - Hemodynamics/drug effects
KW - Hypertension, Pulmonary/pathology
KW - Hypoxia/pathology
KW - Indoles/pharmacology
KW - Lung/pathology
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Monocrotaline/analogs & derivatives
KW - Pneumonectomy
KW - Pyrroles/pharmacology
KW - Vascular Remodeling/drug effects
KW - Sugen 5416
KW - pulmonary hypertension
KW - mice model
KW - monocrotaline pyrrole
KW - pneumonectomy
UR - http://www.scopus.com/inward/record.url?scp=85199812351&partnerID=8YFLogxK
U2 - 10.1152/ajplung.00105.2024
DO - 10.1152/ajplung.00105.2024
M3 - Journal article
C2 - 38810241
SN - 1040-0605
VL - 327
SP - L250-L257
JO - American Journal of Physiology: Lung Cellular and Molecular Physiology
JF - American Journal of Physiology: Lung Cellular and Molecular Physiology
IS - 2
ER -