Modeling Principle

The SD rat veratrine pulmonary arterial hypertension model is a SCI standardized rodent gold-standard pulmonary arterial hypertension (PAH) model established by continuous intraperitoneal injection of veratrine. It accurately recapitulates the complete pathological cascade of clinical idiopathic pulmonary arterial hypertension, including pulmonary arteriole endothelial injury, abnormal proliferation of vascular smooth muscle, pulmonary vascular remodeling, elevated pulmonary circulation resistance, increased pulmonary arterial pressure and compensatory right ventricular hypertrophy, with pathogenesis consistent with the pathogenic pathway of toxin and stress-mediated clinical PAH.

As an alkaloid vascular toxic stimulant, continuous in vivo administration of veratrine targets and injures pulmonary arteriole endothelial cells, destroys the integrity of vascular endothelial barrier, induces burst of endothelial oxidative stress, massive accumulation of ROS and activation of mitochondrial apoptotic pathway. Damaged endothelium secretes abundant vasoconstrictive active factors ET-1 and Ang-Ⅱ, while inhibiting the synthesis and release of vasodilators NO and PGI₂, breaking the vasomotor balance of pulmonary blood vessels and causing persistent spasm and constriction of pulmonary arterioles. Long-term vascular tension disorder continuously stimulates abnormal proliferation and phenotypic transformation of pulmonary arterial smooth muscle cells (PASMCs), massive deposition of collagen and elastic fibers in vascular wall, stenosis of pulmonary arteriole lumen, medial thickening and vascular occlusive remodeling. Progressive elevation of pulmonary circulation resistance leads to significant increase of mean pulmonary arterial pressure (mPAP). Long-term overload pumping of the right ventricle gradually causes right ventricular hypertrophy, right ventricular cavity dilatation and right heart dysfunction, which fully recapitulates the classic disease course of human PAH: endothelial injury-vascular spasm-smooth muscle proliferation-vascular remodeling-pulmonary hypertension-right ventricular hypertrophy and failure.

SD rats possess stable circulating metabolism and clear anatomical layers of pulmonary blood vessels, with synchronous and unified response to veratrine vascular toxicity. The gradients of pulmonary arterial pressure, right ventricular hypertrophy index and pulmonary vascular remodeling degree are stable without spontaneous pulmonary vascular lesions. It can clearly distinguish three-stage lesions of acute endothelial injury stage, progressive vascular remodeling stage and terminal right ventricular hypertrophy stage, and is widely applied to preclinical pharmacodynamic evaluation of drugs for PAH pathogenesis research, pulmonary vascular protection, vascular remodeling inhibition and right cardiac function improvement.

Modeling Success Criteria

Hemodynamics and Cardiac Macroscopic Gross Phenotype

The mPAP and RVSP of blank control rats maintained normal baseline levels, the thickness of left and right ventricles of the heart was uniform without right ventricular dilation and hypertrophy, lung tissues were light pink and soft without stenosis and sclerosis of pulmonary arterioles. At Day 28 terminal point, hemodynamic indexes of model group were extremely significantly elevated with sharp increase of mPAP and RVSP. Obvious dilation and thickening of right ventricle and increased ventricular wall tension could be observed by dissection, and RVHI right ventricular hypertrophy index was significantly higher than blank group. Lung tissues were dark red and hard in texture, with thickened wall and stenotic lumen of hilar and peripheral pulmonary arterioles. Macroscopic vascular remodeling and right ventricular hypertrophy characteristics were visible to naked eye with extremely significant difference from blank group, confirming preliminary successful model construction.

Core Vasoactive, Oxidative and Inflammatory Biochemical Indexes

The contents of vasoconstrictive factors ET-1 and Ang-Ⅱ in lung tissues and serum of model group were extremely significantly upregulated, while the level of vasodilator NO decreased sharply with severe disorder of vasomotor balance. Oxidative damage products ROS and MDA accumulated in lung tissues with reduced antioxidant capacity of SOD and GSH-Px, leading to persistent endothelial oxidative injury. Pro-inflammatory factors TNF-α, IL-6 and IL-1β were persistently highly expressed with sustained activation of chronic vascular inflammation, fully matching the core serological biochemical diagnostic characteristics of clinical PAH: endothelial injury, vasoconstriction dominance and low-grade chronic inflammation.

Pulmonary Vascular Histopathological Characteristics

Combined HE, elastic fiber and Masson staining of lung tissues showed typical vascular remodeling pathological changes of pulmonary arterial hypertension:

1. Day 7 endothelial injury stage: swelling and shedding of pulmonary arteriole endothelial cells, inflammatory cell infiltration in vascular wall and mild vasospasm and constriction;
2. Day 14–21 proliferative remodeling stage: massive proliferation of pulmonary arteriole medial smooth muscle cells, significantly increased medial thickness, progressive lumen stenosis and slight deposition of collagen and elastic fibers;
3. Day 28 terminal remodeling stage: extreme hypertrophy of pulmonary arteriole media, stenotic or even occluded lumen, massive collagen fiber accumulation and disordered broken elastic fibers in vascular adventitia, significantly elevated ratio of pulmonary arteriole wall thickness to lumen diameter, which fully recapitulates characteristic graded pulmonary vascular remodeling lesions of human idiopathic pulmonary arterial hypertension.

Core Vascular Remodeling Pathway Indexes

The expression of smooth muscle proliferation markers α-SMA and PCNA in pulmonary vascular tissues of model group was significantly upregulated, ET-1-mediated MAPK proliferation pathway was persistently overactivated, oxidative stress pathway was unbalanced, and NF-κB pathway of chronic vascular inflammation was activated. Massive synthesis and deposition of vascular extracellular matrix Col-Ⅰ and Col-Ⅲ fully conforms to the complete pathogenic mechanism of veratrine induction: endothelial oxidative injury-vasoconstrictive factor imbalance-smooth muscle proliferation-vascular remodeling-pulmonary arterial hypertension-right ventricular hypertrophy, serving as core academic criterion for confirming successful modeling.

Model Advantages

This model is a SCI-recognized standardized rat model of veratrine-induced pulmonary arterial hypertension with simple modeling operation, which can stably induce persistent pulmonary arterial hypertension via daily intraperitoneal injection and fully recapitulate the whole course of human PAH including endothelial injury, vascular remodeling and right ventricular hypertrophy within 28 days. SD rats possess stable circulatory metabolism, small fluctuation of hemodynamic indexes, uniform vascular remodeling gradient, extremely low intra-group data dispersion and excellent experimental reproducibility. It has pure modeling mechanism relying on alkaloid endothelial toxicity to initiate lesions without confounding inducing factors such as hypoxia, monocrotaline and surgical shunt, with clear targets. It is specially applied to preclinical pharmacodynamic screening of small molecules, traditional Chinese medicine extracts and targeted preparations for pulmonary vascular endothelial protection, smooth muscle proliferation inhibition, vascular remodeling improvement, pulmonary pressure reduction and right ventricular hypertrophy reversal. It features low feeding cost, low operation threshold and large sample size, with data compatible with all high-score cardiovascular SCI journals, suitable for National Natural Science Foundation, master/doctor project opening, graduation thesis and translational medical research of pulmonary arterial hypertension.

Research Applications

The SD rat veratrine pulmonary arterial hypertension model is corely applied to basic research on pulmonary vascular endothelial oxidative injury, ET-1/NO imbalance-mediated vasospasm, abnormal proliferation of pulmonary vascular smooth muscle, extracellular matrix deposition vascular remodeling and compensatory right ventricular hypertrophy. It is specially used for screening and evaluating traditional Chinese medicine compounds, natural active products, small chemical molecules and targeted vasoactive preparations with effects of protecting pulmonary vascular endothelium, balancing vasomotor factors, inhibiting smooth muscle proliferation, alleviating pulmonary arteriole stenosis, reducing pulmonary arterial pressure and reversing right ventricular hypertrophy. It is widely adopted for excavation of pathogenic targets of pulmonary arterial hypertension, elucidation of pulmonary vascular remodeling regulation mechanisms and in-vivo pharmacodynamic verification of anti-PAH drugs, serving as a standardized universal rodent gold-standard model in the fields of cardiovascular pharmacology, pulmonary circulation diseases and vascular remodeling research.

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