Multimodal Assessment of a Hypoxic Pulmonary Hypertension Mouse Model

doi:10.12300/j.issn.1674-5817.2025.181

Abstract

Abstract:

Objective To establish a mouse model of hypoxic pulmonary hypertension (HPH) through intermittent hypoxia induction, and to develop a comprehensive and reliable evaluation system for the HPH model, thereby providing experimental evidence for mechanistic studies and translational applications related to this disease. Methods Twenty-four male specific pathogen-free (SPF) BALB/c mice were randomly divided into a control group and a model group, with 12 mice per group. Mice in the model group were placed in a hypobaric oxygen chamber control system to establish the HPH model, whereas mice in the control group received no intervention. After 28 days of modeling, a comprehensive evaluation of the pathophysiological characteristics of both groups was performed using a general condition scoring scale, echocardiography, hemodynamic measurements, blood gas analysis, hematological tests, organ coefficient determination, histopathological examination, and enzyme-linked immunosorbent assay (ELISA). In addition, correlation analyses were conducted among echocardiographic parameters, the contents of endothelin?1 (ET?1) and N?terminal pro?B?type natriuretic peptide (NT?proBNP) in lung tissue, and other measured indices. Results With prolonged modeling duration time, body weight, water intake, and activity level of mice in the model group were significantly decreased compared with the control group (P<0.05). Echocardiography showed that, compared with the control group, the model group exhibited increased right ventricular dimensions (P<0.01), right ventricular anterior wall thickening (P<0.01), and widened main pulmonary artery diameter (P<0.01), whereas the peak systolic velocity across the pulmonary valve, tricuspid annular plane systolic excursion, and peak systolic velocity of the tricuspid annulus were significantly decreased (P<0.001); tricuspid regurgitation was observed in some model animals. Hemodynamic results revealed that right ventricular systolic pressure was elevated in the model group compared with the control group (P<0.001). Blood gas analysis showed that pH, partial pressure of oxygen, oxygen saturation, actual bicarbonate, and total carbon dioxide were all decreased in the model group compared with the control group (P<0.01). Hematological indices demonstrated that lymphocyte counts (P<0.05) and reticulocyte counts (P<0.001) were decreased in the model group compared with the control group. Compared with the control group, the organ coefficients of heart and lung in the model group were significantly increased (P<0.05 and P<0.001). Pathological examination revealed that the right ventricular hypertrophy index was significantly increased in the model group (P<0.001), with varying degrees of damage to the right ventricle, pulmonary artery, and pulmonary vessels; both the pulmonary artery wall thickness percentage and the pulmonary wall area percentage were significantly elevated (P<0.001). ELISA results showed that the levels of ET?1 and NT?proBNP in lung tissues were significantly increased in the model group compared with the control group (P<0.05 and P<0.001, respectively). Correlation analysis indicated that some echocardiographic parameters were highly correlated with multiple indices in the development of HPH (P<0.05). Conclusion Echocardiography can accurately assess a series of hemodynamic changes in HPH, including right ventricular structural, functional impairment, and pulmonary hypertension. Laboratory tests not only help verify whether the model has been successfully established, but also provide deeper insights into the pathogenesis of HPH, evaluate the effects of interventions, and offer scientific evidence for clinical outcomes. Pathological examination can further confirm the alterations in pulmonary vascular remodeling and increased right heart load. This multimodal analysis provides a reliable animal model and evaluation paradigm for both basic and translational research on HPH, and is of great significance for exploring disease mechanisms and developing precision therapeutic strategies.

Key words: Echocardiography, Hemodynamics, Intermittent hypoxia-induced pulmonary hypertension, Pathological examination, Mice

CLC Number:

R-332

DU Hongzhi,FAN Jin,WEI Xiaolu,et al. Multimodal Assessment of a Hypoxic Pulmonary Hypertension Mouse Model[J]. Laboratory Animal and Comparative Medicine, 2026, 46(4): 476-486. DOI: 10.12300/j.issn.1674-5817.2025.181.

Figures/Tables 8

References 26

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评价维度 Evaluation dimensions	评分标准/分 Scoring criteria/points
评价维度 Evaluation dimensions	0	1	2	3
精神状态 Mental status	精神饱满，反应灵敏，受刺激（如轻触）后迅速回避	精神稍萎靡，反应较迟钝，受刺激后缓慢回避	精神萎靡，嗜睡，刺激后无明显回避反应	精神极度萎靡，处于濒死状态，对刺激无反应
毛发状态 Hair condition	毛发光洁顺滑，紧贴体表，无杂乱、脱毛	毛发略粗糙，少量杂乱，无脱毛	毛发干枯、杂乱，局部蓬松，伴少量脱毛	毛发严重干枯、蓬乱，大面积脱毛或结块
活动度 Activity level	活动频繁，自主探索活跃，笼内穿梭自如	活动减少，多静坐，偶尔穿梭走动	活动极少，仅在摄食饮水时短暂活动，大部分时间蜷缩一隅	几乎无自主活动，蜷缩不动
呼吸状态 Respiratory status	呼吸平稳，胸腹起伏均匀，无异常呼吸音	呼吸频率轻度加快，胸腹起伏略明显，无张口呼吸	呼吸急促，胸腹起伏剧烈，伴轻微张口呼吸或喘鸣	严重呼吸困难，张口呼吸，喘鸣明显，甚至出现发绀（口唇/肢端青紫）
饮食与体况 Diet and body condition	摄食、饮水正常，体重稳定增长，体形匀称	摄食、饮水量轻度下降，体重增长缓慢或无明显变化	摄食、饮水量显著下降，体重下降＞5%，体型偏瘦	几乎不进食、饮水，体重下降＞10%，体型极度消瘦，皮肤弹性差

评价维度 Evaluation dimensions	评分标准/分 Scoring criteria/points
评价维度 Evaluation dimensions	0	1	2	3
精神状态 Mental status	精神饱满，反应灵敏，受刺激（如轻触）后迅速回避	精神稍萎靡，反应较迟钝，受刺激后缓慢回避	精神萎靡，嗜睡，刺激后无明显回避反应	精神极度萎靡，处于濒死状态，对刺激无反应
毛发状态 Hair condition	毛发光洁顺滑，紧贴体表，无杂乱、脱毛	毛发略粗糙，少量杂乱，无脱毛	毛发干枯、杂乱，局部蓬松，伴少量脱毛	毛发严重干枯、蓬乱，大面积脱毛或结块
活动度 Activity level	活动频繁，自主探索活跃，笼内穿梭自如	活动减少，多静坐，偶尔穿梭走动	活动极少，仅在摄食饮水时短暂活动，大部分时间蜷缩一隅	几乎无自主活动，蜷缩不动
呼吸状态 Respiratory status	呼吸平稳，胸腹起伏均匀，无异常呼吸音	呼吸频率轻度加快，胸腹起伏略明显，无张口呼吸	呼吸急促，胸腹起伏剧烈，伴轻微张口呼吸或喘鸣	严重呼吸困难，张口呼吸，喘鸣明显，甚至出现发绀（口唇/肢端青紫）
饮食与体况 Diet and body condition	摄食、饮水正常，体重稳定增长，体形匀称	摄食、饮水量轻度下降，体重增长缓慢或无明显变化	摄食、饮水量显著下降，体重下降＞5%，体型偏瘦	几乎不进食、饮水，体重下降＞10%，体型极度消瘦，皮肤弹性差

指标 Parameters	对照组 Control group	模型组 Model group
RVWT δ/mm	0.35±0.02	0.50±0.10^**
RVAPD l/mm	1.23±0.13	1.59±0.09^***
MPAD l/mm	1.45±0.10	1.69±0.10^***
Vpa /（mm·s^-1）	694.33±41.70	579.48±41.43^***
RVTD l/mm	2.39±0.11	3.07±0.15^***
RVLD l/mm	3.29±0.29	3.87±0.30^**
TAPSV /（mm·s^-1）	63.84±9.02	38.90±8.90^***
TAPSE l/mm	1.17±0.11	0.69±0.24^***

指标 Parameters	对照组 Control group	模型组 Model group
RVWT δ/mm	0.35±0.02	0.50±0.10^**
RVAPD l/mm	1.23±0.13	1.59±0.09^***
MPAD l/mm	1.45±0.10	1.69±0.10^***
Vpa /（mm·s^-1）	694.33±41.70	579.48±41.43^***
RVTD l/mm	2.39±0.11	3.07±0.15^***
RVLD l/mm	3.29±0.29	3.87±0.30^**
TAPSV /（mm·s^-1）	63.84±9.02	38.90±8.90^***
TAPSE l/mm	1.17±0.11	0.69±0.24^***

检测指标 Measured parameters		对照组 Control group	模型组 Model group
右心室收缩压 Right ventricular systolic pressure	RVSP p/mmHg	4.76±0.95	9.46±0.75^***
血气指标 Blood gas indicators	pH	7.037±0.089	6.899±0.045^**
	PCO₂p/mmHg	67.9±4.5	57.6±11.6
	PO₂p/mmHg	108.0±4.0	85.3±4.1^***
	SO₂φ/%	94.2±1.6	85.5±3.8^***
	HCO₃^-c/（mmol·L^-1）	18.0±4.0	10.8±1.7^**
	TCO₂c/(mmol·L^-1)	20.0±3.8	12.0±2.1^**
	a/A	1	1
	Lac c/(mmol·L^-1)	6.59±0.63	9.51±1.13^***
	WBC C_cell /(10⁹·L^-1)	5.12±0.26	7.11±0.81^***
血液学指标 Hematological indicators	RBC C_cell /(10¹²·L^-1)	10.46±0.29	11.31±0.40^**
	PCV φ/%	47.03±0.75	49.57±1.30^**
	HGB ρ/(g·L^-1)	157.33±1.37	169.00±3.46^***
	PLT C_cell /(10⁹·L^-1)	535.67±276.84	1 229.67±90.20^***
	RDW-SD/fL	23.4±0.5	26.1±0.2^***
	RDW-CV/%	19.3±0.3	19.9±0.3^**
	RDW φ/fL	7.53±0.51	8.17±0.40^*
	NEUT C_cell /(10⁹·L^-1)	0.83±0.07	1.46±0.32^**
	LYMPH C_cell /(10⁹·L^-1)	5.39±1.21	3.84±0.44^*
	RET C_cell /(10⁹·L^-1)	3.62±0.27	2.06±0.31^***