The role of vascular injury and hemodynamics in rat pulmonary artery remodeling.

Abstract

Vascular remodeling in adult human elastic pulmonary arteries is characterized by diffuse neointimal lesions containing smooth muscle cells expressing extracellular matrix genes. Recent studies suggest vascular injury is needed to initiate remodeling and that growth factor mediators participate in the repair response. However, because neointimal formation is only observed in patients with pulmonary artery blood pressures approaching systemic levels, it has been hypothesized that systemic-like hemodynamic conditions are also necessary. To test that hypothesis, subclavian-pulmonary artery anastomoses were created in Sprague-Dawley rats under three different experimental conditions: no accompanying injury, or after monocrotaline or balloon endarterectomy injury.Pulmonary vascular remodeling was not induced by the subclavian-pulmonary artery anastomosis alone. A nonneointimal pattern of remodeling after mild monocrotalineinduced injury was converted into a neointimal pattern in the presence of the anastomosis. Neointima was also observed after severe, balloon endarterectomy-induced injury even in the absence of anastomosis. Tropoelastin, type I procollagen and TGF-␤ gene expression, and angiotensin converting enzyme immunoreactivity, was confined to the neointima resembling the pattern of gene expression and immunoreactivity in human hypertensive elastic pulmonary artery neointimal lesions. These observations introduce the concepts that the type of injury and the associated hemodynamic conditions can modify the elastic pulmonary artery response to injury.

Upregulation of collagens detected by gene array in a model of flow-induced pulmonary vascular remodeling

“…The array for ϳ600 human genes (Clontech Atlas Cardiovascular Array) relevant to cardiovascular physiology was applied in conjunction with low-stringency hybridization to promote signal detection across the species barrier. Using this approach, we identified and confirmed upregulation of collagen 1 ␣1 (COL1A1) in shunted pulmonary arteries, which is in accordance with a rat model of pulmonary hypertension (51). In addition, we identified a number of other putative alterations in gene expression and confirmed upregulation at the mRNA as well as protein levels of a second collagen protein, procollagen ␣1 (III) (COL3A1).…”

“…It was necessary to confirm the fidelity of hybridization of the array by using homologous probes. The results in Table 1 indicate upregulation of four types of collagen, including COL1A1, which had been previously reported to be induced in a rat model of pulmonary hypertension (4,51). A partial sequence of the corresponding pig homologue was available along with a partial sequence of pig COL3A1.…”

“…Much of the work on vascular remodeling in the lung has focused on the long-term effects of hypoxia-induced vasoconstriction, globally increased pulmonary vascular flow (e.g., produced by ligation of the ductus arteriosus in fetal lambs), or chemically induced pulmonary hypertension (e.g monocrotaline) (4,44,48,50,51,53). Whereas useful, each of these models has significant limitations, such as difficulty separating the effects of high flow from the proconstrictive agent, Fig.…”

“…However, despite the presence of numerous animal models, pathways examining the mechanisms that underlie pulmonary vasculopathy in the lung vessels remain poorly defined at the molecular level (4). A few candidate genes involved in tissue remodeling such as elastase, tenascin (37,38), tropoelastin, and type I procollagen have been investigated in organ culture and a rat model of pulmonary hypertension (4,51). However, correlation between histological evidence of flow-induced pulmonary vasculopathy and changes in gene expression in animal models is needed.…”

Pulmonary vascular involvement in chronic obstructive pulmonary disease

“…It is of interest that a 1 -antitrypsin treatment of adult rats prevents the development of VEGF-receptor blockade-induced lung capillary loss [50]. The current authors also believe that endothelial cells and vascular smooth muscle cells form a "functional" syncytium [36], yet the intricate interactions on a molecular level between growth factors [59][60][61][62][63], haemodynamic variables, vascular injury [64], hypoxia [36,65,66] proteases [49,67] and control of apoptosis [43,49], and how they affect the so-called vascular remodelling, are still largely unclear.…”