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Experimental and Transgenic Models of Pulmonary Hypertension

James West, Anna Hemnes

10.1002/cphy.c100003

Source: Volume 1, Issue 2, April 2011

Published online: April 2011

Full Article on Wiley Online Library



Abstract

Pulmonary hypertension in human patients can result from increased pulmonary vascular tone, pressure transferred from the systemic circulation, dropout of small pulmonary vessels, occlusion of vessels with thrombi or intimal lesions, or some combination of all of these. Different animal models have been designed to reflect these different mechanistic origins of disease. Pulmonary hypertension models may be roughly grouped into tone‐related models, inflammation‐related models, and genetic models with unusual or mixed mechanism. Models of tone generally use hypoxia as a base, and then modify this with either genetic modifications (SOD, NOS, and caveolin) or with drugs (Sugen), although some genetic modifications of tone‐related pathways can result in spontaneous pulmonary hypertension (Hph‐1). Inflammation‐related models can use either toxic chemicals (monocrotaline, bleomycin), live pathogens (stachybotrys, schistosomiasis), or genetic modifications (IL‐6, VIP). Additional genetic models rely on alterations in metabolism (adiponectin), cell migration (S100A4), the serotonin pathway, or the BMP pathway. While each of these shares molecular and pathologic symptoms with different classes of human pulmonary hypertension, in most cases the molecular etiology of human pulmonary hypertension is unknown, and so the relationship between any model and human disease is unclear. There is thus no best animal model of pulmonary hypertension; instead, investigators must select the model most related to the specific pathology they are studying. © 2011 American Physiological Society. Compr Physiol 1:769‐782, 2011.

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Figure 1. Figure 1.

Primary sources of increased pulmonary vascular resistance. Smooth muscle cells are color‐coded green, endothelium red, and cells of mixed or unknown origin yellow, with nucleii blue (A) normal murine pulmonary arteries lack adventitia, and elastic lamina is generally not visible without specific staining. Vessels below 25 μm in size are rarely muscularized; about one‐third of vessels in the range of 25 to 75 μm in size are muscularized. With partially muscularized vessels, smooth muscle is wrapped in a helix around the length of a vessel, and thus appears to leave part of the vessel uncovered in cross‐section. (B) Relatively mild constriction, in terms of % reduction in radius (r), can lead to much more dramatic increases in pulmonary vascular resistance and shear stress. Since area changes as r2 and shear stress changes inversely with r4, a 30% decrease in area results in a 2‐fold decrease in vessel area and a 4‐fold increase in shear stress. (C) Remodeling in response to sustained high pressure or inflammatory insults results in hypertrophy of existing smooth muscle, and increased muscularization either through migration, transdifferentiation, or proliferation (this is not settled in the literature). In addition, vessels are stiffened through deposition of additional matrix; this is difficult to see in muring pulmonary vessels, but may result in increased dynamic resistance through loss of compliance to pressure waves. (D) Vessels may also be obstructed through thrombus formation (not shown) or through accumulation of cells in the intima or lumen. These cells may arise through proliferation, transdifferentiation and migration, or recruitment of circulating cells—the relative importance of these mechanisms is an area of ongoing study.
Figure 2. Figure 2.

Shunt exposes the pulmonary vasculature to increased flow and consequent shear stress. This causes endothelial damage, with resulting inflammation, conventional remodeling, and possible intimal lesions through failed attempts at angiogenesis.
Figure 3. Figure 3.

Pulmonary hypertension can be driven primarily by vasoconstriction, due to hypoxic vasoconstriction or alteration in factors that directly regulate tone, such as endothelin, nitric oxide, or nitric‐oxide pathway genes. In these models, sustained constriction leads to increased pressure and shear stress, resulting in inflammation, conventional remodeling, and in extreme cases formation of intimal lesions.
Figure 4. Figure 4.

The pulmonary vasculature responds to damage or chronic inflammation through initiating a program of remodeling, including hypertrophy, neomuscularization, and under some conditions creation of intimal lesions. In these cases, increased RVSP may not develop until the remodeling program is far advanced.
Figure 5. Figure 5.

Normal response‐to‐acute vascular injury includes cellular shift to a synthetic state, with altered metabolism, to support proliferation coupled with changes in actin organization to allow migration and recruitment of inflammatory cells. Mutations in genes directing these pathways (depicted in colors) result in a pathologic inability to properly terminate or direct these processes, leading to loss of vessel patency and pulmonary hypertension.


Figure 1.

Primary sources of increased pulmonary vascular resistance. Smooth muscle cells are color‐coded green, endothelium red, and cells of mixed or unknown origin yellow, with nucleii blue (A) normal murine pulmonary arteries lack adventitia, and elastic lamina is generally not visible without specific staining. Vessels below 25 μm in size are rarely muscularized; about one‐third of vessels in the range of 25 to 75 μm in size are muscularized. With partially muscularized vessels, smooth muscle is wrapped in a helix around the length of a vessel, and thus appears to leave part of the vessel uncovered in cross‐section. (B) Relatively mild constriction, in terms of % reduction in radius (r), can lead to much more dramatic increases in pulmonary vascular resistance and shear stress. Since area changes as r2 and shear stress changes inversely with r4, a 30% decrease in area results in a 2‐fold decrease in vessel area and a 4‐fold increase in shear stress. (C) Remodeling in response to sustained high pressure or inflammatory insults results in hypertrophy of existing smooth muscle, and increased muscularization either through migration, transdifferentiation, or proliferation (this is not settled in the literature). In addition, vessels are stiffened through deposition of additional matrix; this is difficult to see in muring pulmonary vessels, but may result in increased dynamic resistance through loss of compliance to pressure waves. (D) Vessels may also be obstructed through thrombus formation (not shown) or through accumulation of cells in the intima or lumen. These cells may arise through proliferation, transdifferentiation and migration, or recruitment of circulating cells—the relative importance of these mechanisms is an area of ongoing study.



Figure 2.

Shunt exposes the pulmonary vasculature to increased flow and consequent shear stress. This causes endothelial damage, with resulting inflammation, conventional remodeling, and possible intimal lesions through failed attempts at angiogenesis.



Figure 3.

Pulmonary hypertension can be driven primarily by vasoconstriction, due to hypoxic vasoconstriction or alteration in factors that directly regulate tone, such as endothelin, nitric oxide, or nitric‐oxide pathway genes. In these models, sustained constriction leads to increased pressure and shear stress, resulting in inflammation, conventional remodeling, and in extreme cases formation of intimal lesions.



Figure 4.

The pulmonary vasculature responds to damage or chronic inflammation through initiating a program of remodeling, including hypertrophy, neomuscularization, and under some conditions creation of intimal lesions. In these cases, increased RVSP may not develop until the remodeling program is far advanced.



Figure 5.

Normal response‐to‐acute vascular injury includes cellular shift to a synthetic state, with altered metabolism, to support proliferation coupled with changes in actin organization to allow migration and recruitment of inflammatory cells. Mutations in genes directing these pathways (depicted in colors) result in a pathologic inability to properly terminate or direct these processes, leading to loss of vessel patency and pulmonary hypertension.

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Article Title: Experimental and Transgenic Models of Pulmonary Hypertension
 

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James West, Anna Hemnes. Experimental and Transgenic Models of Pulmonary Hypertension. Compr Physiol 2011, 1: 769-782. doi: 10.1002/cphy.c100003