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. 2013 Jan;12(1):33-42.
doi: 10.1007/s10237-012-0379-6.

Patchy deletion of Bmpr1a potentiates proximal pulmonary artery remodeling in mice exposed to chronic hypoxia

Rebecca R Vanderpool  1 , Nesrine El-Bizri, Marlene Rabinovitch, Naomi C Chesler
Affiliations

Patchy deletion of Bmpr1a potentiates proximal pulmonary artery remodeling in mice exposed to chronic hypoxia

Rebecca R Vanderpool et al. Biomech Model Mechanobiol. 2013 Jan.

Abstract

Reduced vascular expression of bone morphogenetic protein type IA receptor (Bmpr1a) has been found in patients with pulmonary arterial hypertension. Our previous studies in mice with patchy deletion of Bmpr1a in vascular smooth muscle cells and cardiac myocytes showed decreased distal vascular remodeling despite a similar severity of hypoxic pulmonary hypertension (HPH). We speculate increased stiffness from ectopic deposition of collagen in proximal pulmonary arteries might account for HPH. Pulsatile pressure-flow relationships were measured in isolated, ventilated, perfused lungs of SM22α;TRE-Cre;R26R;Bmpr1a(flox/flox) (KO) mice and wild-type littermates, following 21 days (hypoxia) and 0 days (control) of chronic hypoxia. Pulmonary vascular impedance, which yields insight into proximal and distal arterial remodeling, was calculated. Reduced Bmpr1a expression had no effect on input impedance Z(0) (P = 0.52) or characteristic impedance Z(C) (P = 0.18) under control conditions; it also had no effect on the decrease in Z(0) via acute rho kinase inhibition. However, following chronic hypoxia, reduced Bmpr1a expression increased Z(C) (P < 0.001) without affecting Z(0) (P = 0.72). These results demonstrate that Bmpr1a deficiency does not significantly alter the hemodynamic function of the distal vasculature or its response to chronic hypoxia but larger, more proximal arteries are affected. In particular, reduced Bmpr1a expression likely decreased dilatation and increased stiffening in response to hypoxia, probably by collagen accumulation. Increased PA stiffness can have a significant impact on right ventricular function. This study illustrates for the first time how proximal pulmonary artery changes in the absence of distal pulmonary artery changes contribute to pulmonary arterial hypertension.

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Figures

Figure 1
Figure 1
Mean pulmonary artery pressure (mPAP) measured in response to steady flow (Q=3 ml/min) in control and hypoxic KO (control: n = 6, hypoxic: n = 5) and WT (control: n = 5, hypoxic: n = 4) mouse lungs in the baseline SMC tone state and with Y27632. * P<0.05 vs. control; † P<0.05 Y27632 vs. baseline.
Figure 2
Figure 2
Pulmonary vascular impedance magnitude (Z) and phase (θ) spectra in control and hypoxic KO and WT mouse lungs in the baseline smooth muscle tone state and with Y27632from A) and D) control and B) and E) hypoxic mouse lungs (WT: A, B C; KO: D, E, F) in a baseline state and with Y27632.
Figure 3
Figure 3
Input impedance (Z0; top) and characteristic impedance (ZC; bottom) for each individual control and hypoxic mouse in both the WT and KO strains in the baseline SMC tone state and with Y27632. * P<0.05 vs. 0-day; † P<0.05 Y27632 vs. baseline.
Figure 4
Figure 4
Representative experimental and theoretical ZC-mean PAP relationships for each strain (C57BL6, WT and KO) and hypoxic exposure (C57BL6: 10 days, WT and KO: 21 days) when a theoretical D0, h0 and E is found for each individual mouse. The extrema of the solution spaces for the theoretical ZC-mPAP relationships are shown by the bounding areas.
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