A Novel Murine Model of Severe Pulmonary Arterial Hypertension

Ciuclan, Loredana; Bonneau, Olivier; Hussey, Martin; Duggan, Nicholas; Holmes, Alan M.; Good, Robert B.; Stringer, Rowan; Jones, Peter; Morrell, Nicholas W.; Járai, Gábor; Walker, Christoph; Westwick, John; Thomas, Matthew

doi:10.1164/rccm.201103-0412oc

Cited by 228 publications

(274 citation statements)

References 45 publications

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“…While we found a small number of occlusive arteriolar lesions in SuHx mice and none in normoxic or VehHx mice 10 weeks after the end of hypoxia, these were very rare and thus unlikely to have contributed greatly to PH in these animals. In contrast to Ciuclan et al, 6 we did not observe any angiobliterative lesions in SuHx mice after 3 weeks of hypoxia. Hence, according to our results, SuHx produces sustained PH and moderate RV dysfunction as judged by TAPSE but no significant angioobliterative pulmonary vascular disease in mice.…”

Section: Discussioncontrasting

confidence: 99%

The Sugen 5416/Hypoxia Mouse Model of Pulmonary Hypertension Revisited: Long‐Term Follow‐Up

et al. 2014

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a SHV and GH contributed equally to this work.Abstract: The combination of a vascular endothelial growth factor receptor antagonist, Sugen 5416 (SU5416), and chronic hypoxia is known to cause pronounced pulmonary hypertension (PH) with angioobliterative lesions in rats and leads to exaggerated PH in mice as well. We sought to determine whether weekly SU5416 injections during 3 weeks of hypoxia leads to long-term development of angioobliterative lesions and sustained or progressive PH in mice. Male C57BL/6J mice were injected with SU5416 (SuHx) or vehicle (VehHx) weekly during 3 weeks of exposure to 10% oxygen. Echocardiographic and invasive measures of hemodynamics and pulmonary vascular morphometry were performed after the 3-week hypoxic exposure and after 10 weeks of recovery in normoxia. SuHx led to higher right ventricular (RV) systolic pressure and RV hypertrophy than VehHx after 3 weeks of hypoxia. Ten weeks after hypoxic exposure, RV systolic pressure decreased but remained elevated in SuHx mice compared with VehHx or normoxic control mice, but RV hypertrophy had resolved. After 3 weeks of hypoxia and 10 weeks of followup in normoxia, tricuspid annular plane systolic excursion was significantly decreased, indicating decreased systolic RV function. Very few angioobliterative lesions were found at the 10-week follow-up time point in SuHx mouse lungs. In conclusion, SU5416 combined with 3 weeks of hypoxia causes a more profound PH phenotype in mice than hypoxia alone. PH persists over 10 weeks of normoxic follow-up in SuHx mice, but significant angioobliterative lesions do not occur, and neither PH nor RV dysfunction worsens. The SuHx mouse model is a useful adjunct to other PH models, but the search will continue for a mouse model that better recapitulates the human phenotype.

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Section: Discussioncontrasting

confidence: 99%

The Sugen 5416/Hypoxia Mouse Model of Pulmonary Hypertension Revisited: Long‐Term Follow‐Up

et al. 2014

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“…While this is higher than values normally reported at sea level (around 20%; Ciuclan et al, 2011), it is much lower than the values reported in rats in our present and past (Lumbroso et al, 2012) studies. Protection against elevated pulmonary hypertension is common in species adapted to high altitude, which demonstrate thinner pulmonary vessel walls with a reduced number of muscular cells (Tucker and Rhodes, 2001).…”

Section: Discussioncontrasting

confidence: 84%

Divergent physiological responses in laboratory rats and mice raised at high altitude

Jochmans-Lemoine

Villalpando

Gonzales

et al. 2015

Journal of Experimental Biology

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Ecological studies show that mice can be found at high altitude (HAup to 4000 m) while rats are absent at these altitudes, and there are no data to explain this discrepancy. We used adult laboratory rats and mice that have been raised for more than 30 generations in La Paz, Bolivia (3600 m), and compared their hematocrit levels, right ventricular hypertrophy (index of pulmonary hypertension) and alveolar surface area in the lungs. We also used whole-body plethysmography, indirect calorimetry and pulse oxymetry to measure ventilation, metabolic rate (O 2 consumption and CO 2 production), heart rate and pulse oxymetry oxygen saturation (p O2,sat ) under ambient conditions, and in response to exposure to sea level P O2 (32% O 2 =160 mmHg for 10 min) and hypoxia (18% and 15% O 2 =90 and 75 mmHg for 10 min each). The variables used for comparisons between species were corrected for body mass using standard allometric equations, and are termed mass-corrected variables. Under baseline, compared with rats, adult mice had similar levels of p O2,sat , but lower hematocrit and hemoglobin levels, reduced right ventricular hypertrophy and higher mass-corrected alveolar surface area, tidal volume and metabolic rate. In response to sea level P O2 and hypoxia, mice and rats had similar changes of ventilation, but metabolic rate decreased much more in hypoxia in mice, while p O2,sat remained higher in mice. We conclude that laboratory mice and rats that have been raised at HA for >30 generations have different physiological responses to altitude. These differences might explain the different altitude distribution observed in wild rats and mice.

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“…For example, in the Sugen5416/hypoxia mouse model of PAH, the increase in RVSP values from 32 to 50 mmHg was induced when >60% of pulmonary arterioles were affected by muscularization (27% partial muscularization and 37% full muscularization). 32 In fact, our data are similar to other murine models showing that pulmonary arterial remodeling, even when present at an advanced degree, does not necessarily cause pulmonary hypertension. 33 These observations support the clinical studies showing that pulmonary vascular remodeling has limited diagnostic value because they are present in all forms of severity of pulmonary hypertension 27 ; it may explain, at least to some extent, the discrepancy between significant vascular remodeling associated with only mild elevation of pulmonary arterial pressure, often observed in PAH patients.…”

Section: Treatment Of K0supporting

confidence: 89%

Modulation of Intersectin-1s Lung Expression Induces Obliterative Remodeling and Severe Plexiform Arteriopathy in the Murine Pulmonary Vascular Bed

Patel

Predescu

Bardita

et al. 2017

The American Journal of Pathology

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Murine models of pulmonary arterial hypertension (PAH) that recapitulate the plexiform and obliterative arteriopathy seen in PAH patients and help in defining the molecular mechanisms involved are missing. Herein, we investigated whether intersectin-1s (ITSN) deficiency and prolonged lung expression of an ITSN fragment with endothelial cell (EC) proliferative potential (EH ITSN ), present in the lungs of PAH animal models and human patients, induce formation of plexiform/obliterative lesions and defined the molecular mechanisms involved. ITSN-deficient mice (knockout/heterozygous and knockdown) were subjected to targeted lung delivery of EH ITSN via liposomes for 20 days. Immunohistochemistry and histological and morphometric analyses revealed a twofold increase in proliferative ECs and a 1.35-fold increase in proliferative a-smooth muscle actinepositive cells in the lungs of ITSNdeficient mice, transduced with the EH ITSN relative to wild-type littermates. Treated mice developed severe medial wall hypertrophy, intima proliferation, and various forms of obliterative and plexiformlike lesions in pulmonary arteries, similar to PAH patients. Hemodynamic measurements indicated modest increases in the right ventricular systolic pressure and right ventricle hypertrophy. Transcriptional and protein assays of lung tissue indicated p38 MAPK -dependent activation of Elk-1 transcription factor and increased expression of c-Fos gene. This unique murine model of PAH-like plexiform/obliterative arteriopathy induced via a two-hit pathophysiological mechanism without hypoxia provides novel druggable targets to ameliorate and, perhaps, reverse the EC plexiform phenotype in severe human PAH. Pulmonary arterial hypertension (PAH) is a severe human disease characterized by narrowing of the small pulmonary arteries, leading to a progressive increase in pulmonary vascular resistance, which frequently leads to right-sided heart failure and death.1e3 A common histological finding in patients with severe PAH is the presence of plexiform lesions that obliterate the small to mid-sized pulmonary arterioles. 4,5 The plexiform pulmonary vascular lesions found at branching points in the small pulmonary arterioles are lumen-obliterating, glomeruloid-like vascular structures, predominantly composed of actively dividing and phenotypically abnormal apoptosis-resistant endothelial cells (ECs).6,7 The cellular and molecular mechanisms responsible for the development of plexiform lesions are poorly understood.Recent evidence suggests the involvement of inflammatory mechanisms in the development of PAH. 8 Studies have indicated that inflammation associated with human PAH Supported by NIH grants R01 HL089462 (S.P.) and R01 HL0127022 (S.P.).Disclosures: None declared.

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A Novel Murine Model of Severe Pulmonary Arterial Hypertension

Abstract: These data describe a novel murine model of PAH, which displays many of the hallmarks of the human disease, thus opening new avenues of investigation to better understand PAH pathophysiology.

Cited by 228 publications

References 45 publications

The Sugen 5416/Hypoxia Mouse Model of Pulmonary Hypertension Revisited: Long‐Term Follow‐Up

The Sugen 5416/Hypoxia Mouse Model of Pulmonary Hypertension Revisited: Long‐Term Follow‐Up

Divergent physiological responses in laboratory rats and mice raised at high altitude

Modulation of Intersectin-1s Lung Expression Induces Obliterative Remodeling and Severe Plexiform Arteriopathy in the Murine Pulmonary Vascular Bed

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