Gelatinase expression in pulmonary arteries during experimental pulmonary hypertension

Abstract

Structural remodelling of pulmonary vessels is an important feature of pulmonary hypertension (PH), which reflects distal artery muscularization and matrix remodelling. The matrix metalloproteinases (MMPs) are involved in extracellular matrix turnover and hence, in smooth muscle cell migration and endothelial cell migration and proliferation. Among the MMPs, gelatinases (MMP-2 and MMP-9) can degrade basement membrane components and promote cell proliferation and migration.This study evaluated gelatinases in pulmonary vessels during progressive PH in two rat models: exposure to hypoxia or monocrotaline.Zymography of tissue homogenates revealed an association of progression of hypoxic PH with a time-dependent increase in gelatinase MMP-2 activity, specific to pulmonary vessels. Increased MMP-2 activity was also found 30 days postmonocrotaline. Reverse transcription polymerase chain reaction demonstrated upregulation of MMP-2 messenger ribonucleic acid. Immunolocalization showed MMP-2 throughout the pulmonary vasculature, from the trunk to the distal vessels, with strong staining of the intima, media and adventitia. MMP-2 was found in its active form and gelatinolytic activity was correlated to PH severity. Activity localization by in situ zymography corroborated with the immunolocalization findings.In conclusion, the authors demonstrated that matrix metalloproteinase-2 activity is increased in pulmonary vessels during progression of pulmonary hypertension, probably as a result of involvement in the matrix turnover associated with vascular remodelling during pulmonary hypertension.

Circulating matrix metalloproteinases and tissue inhibitors of metalloproteinases levels in pediatric patients with congenital heart disease: Relationship to cardiac functions

“…In the studies which were generally conducted in experimental animal models and in scattered human studies with the different etiologies of pulmonary hypertension, matrix metalloproteinase-2 activity, usually, was found to be higher (13,29,34). However, results related to matrix metalloproteinase-9 activity are generally conflicted (29,31).…”

“…It has been shown that elastin degradation is an early pulmonary vascular abnormality in the patients with congenital heart disease associated with pulmonary arterial hypertension (31). Frisdal et al (29) identified increased matrix metalloproteinase-2 expression and activity in rats with pulmonary hypertension by exposure to chronic hypoxia or monocrotaline. The authors enounced that matrix metalloproteinase expression might be modulated by cytokines, most notably interleukin-1α, which are induced by monocrotaline and hypoxia related inflammatory processes.…”

“…In some studies, matrix metalloproteinases were found to contribute to the development of pulmonary arterial hypertension in animals but differences in the effects of matrix metalloproteinase inhibitors were observed between studies. Knowledge about matrix metalloproteinase/ tissue inhibitors of matrix metalloproteinase balance in humans with idiopathic pulmonary arterial hypertension is limited (25)(26)(27)(28)(29).…”

Hypoxic Pulmonary Arterial Hypertension in the Chicken Model

“…MMPs are matrix-degrading enzymes involved in extracellular matrix turnover, smooth muscle cell and endothelial cell migration and proliferation. Increased MMP-2 activity in the pulmonary vessels of hypoxic rats was shown to be associated with the severity of PH (Frisdal et al, 2001). In addition, Herget et al (2003) reported that inhibition of MMP activity attenuated pulmonary vascular remodeling as well as hypertension in chronically hypoxic rats, and suggested that the increased MMP activity might represent a substantial factor mediating the effect of hypoxia on the development of PH.…”

Effects of angiotensin II intervention on MMP-2, MMP-9, TIMP-1, and collagen expression in rats with pulmonary hypertension

“…MMP-2 and MMP-9 can degrade components of basilemmal membranes, mainly type IV collagen, promote the proliferation and migration of SMCs, and participate in the turn-over of type IV collagen (Frisdal et al, 2001). The MMP/TIMP ratio is an accurate indicator of lung tissue repair and determines PVR progress (Li et al, 2011;Tang et al, 2011).…”