Compartment-specific expression of collagens and their processing enzymes in intrapulmonary arteries of IPAH patients

Abstract

Alterations in extracellular matrix (ECM) have been implicated in the pathophysiology of pulmonary hypertension. Here, we have undertaken a compartment-specific study to elucidate the expression profile of collagens and their processing enzymes in donor and idiopathic pulmonary arterial hypertension (IPAH) pulmonary arteries. Predominant intimal, but also medial and perivascular, remodeling and reduced lumen diameter were detected in IPAH pulmonary arteries. Two-photon microscopy demonstrated accumulation of collagen fibers. Quantification of collagen in pulmonary arteries revealed collagen accumulation mainly in the intima of IPAH pulmonary arteries compared with donors. Laser capture-microdissected pulmonary artery profiles (intima+media and perivascular tissue) were analyzed by real-time PCR for ECM gene expression. In the intima+media of IPAH vessels, collagens (COL4A5, COL14A1, and COL18A1), matrix metalloproteinase (MMP) 19, and a disintegrin and metalloprotease (ADAM) 33 were higher expressed, whereas MMP10, ADAM17, TIMP1, and TIMP3 were less abundant. Localization of COLXVIII, its cleavage product endostatin, and MMP10, ADAM33, and TIMP1 was confirmed in pulmonary arteries by immunohistochemistry. ELISA for collagen XVIII/endostatin demonstrated significantly elevated plasma levels in IPAH patients compared with donors, whereas circulating MMP10, ADAM33, and TIMP1 levels were similar between the two groups. Endostatin levels were correlated with pulmonary arterial wedge pressure, and established prognostic markers of IPAH, right atrial pressure, cardiac index, 6-min walking distance, NH2-terminal pro-brain natriuretic peptide, and uric acid. Expression of unstudied collagens, MMPs, ADAMs, and TIMPs were found to be significantly altered in IPAH intima+media. Elevated levels of circulating collagen XVIII/endostatin are associated with markers of a poor prognosis.

Resident cell lineages are preserved in pulmonary vascular remodeling

“…The validity of PDGFRα as an adventitial fibroblast marker was further confirmed on human samples but, similar to the murine models, showed no significant overlap with SMC markers. Consistent with these results are reports from IPAH and PH patients with associated lung diseases showing only limited adventitial thickening . Therefore, the structural contribution of adventitial fibroblast‐derived SMC‐like cells to pulmonary vascular remodeling may represent a very rare event.…”

Role of Stromelysin 2 (Matrix Metalloproteinase 10) as a Novel Mediator of Vascular Remodeling Underlying Pulmonary Hypertension Associated With Systemic Sclerosis

“…Overexpression of MMP10 may be promoted by growth factors, including vascular endothelial growth factor (31), PDGF (35), or bone morphogenetic proteins (BMPs), especially BMP-4 (42). MMP10 expression was also found to be overabundant in perivascular macrophages and pulmonary vascular cells from the remodeled walls of distal pulmonary arteries in patients with SSc-associated PH, which is consistent with the recently reported localization of MMP10 in pulmonary arteries of patients with iPAH (38). Indeed, MMP10 was the single MMP significantly 2218 AVOUAC ET AL overexpressed in SSc EPC-derived ECs (results available upon request from the corresponding author).…”

“…However, we identified up-regulation of MMP10, a multifunctional MMP that superactivates procollagenases, which are involved in skeletal development, wound healing, and vascular remodeling (33). Increased MMP10 levels were detected in the serum of patients with SSc-associated PH, which is consistent with the observed increase in levels of other proMMPs or MMPs previously detected in patients with iPAH (38,43,44), and MMP10 serum levels correlated with several clinical outcomes. Our data indicated that overabundant MMP10 plays a significant role in the progression of vascular complications in SSc.…”

Update in Pulmonary Vascular Disease 2015

“…In other works this year on biomarkers in pulmonary vascular disease, elevated levels of the angiostatic peptide endostatin (ES), which induces endothelial cell proliferation and migration, were observed in plasma and pulmonary arterioles from patients with PAH (18). In a derivation cohort of 84 patients with idiopathic PAH (iPAH) or connective tissue disease, plasma ES levels correlated modestly with mPAP (r = 0.3, P , 0.005) and PVR (r = 0.3, P , 0.005), while ES levels equal to or exceeding 66 ng/ml corresponded to an increase in unadjusted mortality in PAH (hazard ratio, 3.7; 95% confidence interval, 1.5-9.2; logrank P = 0.001) that was directionally similar to observations from a validation cohort of patients with PAH (19).…”