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Research Papers

The Role of Collagen Synthesis in Ventricular and Vascular Adaptation to Hypoxic Pulmonary Hypertension

[+] Author and Article Information
David Schreier

Department of Biomedical Engineering,
University of Wisconsin,
2145 ECB, 1550 Engineering Drive,
Madison, WI 53706

Gouqing Song

Department of Medicine,
Medical Science Center,
University of Wisconsin,
1300 University Avenue,
Madison, WI 53706

Naomi Chesler

Department of Biomedical Engineering,
University of Wisconsin,
2146 ECB, 1550 Engineering Drive,
Madison, WI 53706;
Department of Medicine,
Medical Science Center,
University of Wisconsin,
1300 University Avenue,
Madison, WI 53706
e-mail: chesler@engr.wisc.edu

1Corresponding author. Present address: 2146 Engineering Centers Building, 1550 Engineering Drive, Madison, WI 53706.

Contributed by the Bioengineering Division of ASME for publication in the Journal of Biomechanical Engineering. Manuscript received November 20, 2012; final manuscript received January 17, 2013; accepted manuscript posted January 22, 2013; published online February 7, 2013. Editor: Victor H. Barocas.

J Biomech Eng 135(2), 021018 (Feb 07, 2013) (7 pages) Paper No: BIO-12-1576; doi: 10.1115/1.4023480 History: Received November 20, 2012; Revised January 17, 2013; Accepted January 22, 2013

Pulmonary arterial hypertension (PAH) is a rapidly fatal disease in which mortality is typically due to right ventricular (RV) failure. An excellent predictor of mortality in PAH is proximal pulmonary artery stiffening, which is mediated by collagen accumulation in hypoxia-induced pulmonary hypertension (HPH) in mice. We sought to investigate the impact of limiting vascular and ventricular collagen accumulation on RV function and the hemodynamic coupling efficiency between the RV and pulmonary vasculature. Inbred mice were exposed to chronic hypoxia for 10 days with either no treatment (HPH) or with treatment with a proline analog that impairs collagen synthesis (CHOP-PEG; HPH + CP). Both groups were compared to control mice (CTL) exposed only to normoxia (no treatment). An admittance catheter was used to measure pressure-volume loops at baseline and during vena cava occlusion, with mice ventilated with either room air or 8% oxygen, from which pulmonary hemodynamics, RV function, and ventricular-vascular coupling efficiency (ηvvc) were calculated. Proline analog treatment limited increases in RV afterload (neither effective arterial elastance Ea nor total pulmonary vascular resistance significantly increased compared to CTL with CHOP-PEG), limited the development of pulmonary hypertension (CHOP-PEG reduced right ventricular systolic pressure by 10% compared to HPH, p < 0.05), and limited RV hypertrophy (CHOP-PEG reduced RV mass by 18% compared to HPH, p < 0.005). In an acutely hypoxic state, treatment improved RV function (CHOP-PEG increased end-systolic elastance Ees by 43%, p < 0.05) and maintained ηvvc at control, room air levels. CHOP-PEG also decreased lung collagen content by 12% measured biochemically compared to HPH (p < 0.01), with differences evident in large and small pulmonary arteries by histology. Our results demonstrate that preventing new collagen synthesis limits pulmonary hypertension development by reducing collagen accumulation in the pulmonary arteries that affect RV afterload. In particular, the proline analog limited structural and functional changes in distal pulmonary arteries in this model of early and somewhat mild pulmonary hypertension. We conclude that collagen plays an important role in small pulmonary artery remodeling and, thereby, affects RV structure and function changes induced by chronic hypoxia.

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Figures

Grahic Jump Location
Fig. 1

Pressure-volume loops obtained in a representative (CTL) mouse right ventricle during vena cava occlusion. Ees is obtained graphically as shown during VCO in the right panel.

Grahic Jump Location
Fig. 2

Hydroxyproline content of right lungs from CTL, HPH, and HPH + CP groups. *P < 0.05 versus HPH

Grahic Jump Location
Fig. 3

Representative histology images of picosirius red stain for collagen in (a)–(c) RPA for CTL (a), HPH (b), HPH + CP (c); (d)–(f) lung for CTL (d), HPH (e), HPH + CP (f); and (g)–(i) RV for CTL (g), HPH (h), HPH + CP (i). Black arrows indicate pulmonary arteries in close proximity to large airways, and white arrow indicates a pulmonary vein surrounded by alveoli. Note, only the black arrow in panel (e) demonstrates significant collagen accumulation. Scale bar is 0.1 mm for all images.

Grahic Jump Location
Fig. 4

Right ventricular systolic pressure for CTL, HPH, and HPH + CP groups during room air ventilation. P < 0.05 versus CTL; *P < 0.05 versus HPH.

Grahic Jump Location
Fig. 5

(a) Ees, (b) Ea, and (c) VVC efficiency for CTL, HPH, and HPH + CP groups. P < 0.05 versus CTL; *P < 0.05 versus HPH, §P < 0.05 versus room air.

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