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

Compartment-specific expression of collagens and their processing enzymes in intrapulmonary arteries of IPAH patients
Compartment-specific expression of collagens and their processing enzymes in intrapulmonary arteries of IPAH patients
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.
vascular remodeling, vascular fibrosis, laser microdissection, collagen xviii, endostatin
1040-0605
L1002-L1013
Hoffmann, Julia
63ae071e-6886-40b3-a4f8-abf0c5c6573b
Marsh, Leigh M.
993ee686-f303-4994-9f49-14ae3fbdcc42
Pieper, Mario
39dd94fc-600d-4093-82fe-30ed6601812d
Stacher, Elvira
03071ea9-2c92-4a96-b645-c18a7d184675
Ghanim, Bahil
e19d471c-be9c-463a-81f3-885dea1fb44a
Kovacs, Gabor
703ce405-347a-4f27-b194-f59365ce053c
König, Peter
3cdc95dc-0345-4024-8241-5c1d14a76d1d
Wilkens, Heinrike
76701aa4-c627-46dc-a07e-5bfc9603c794
Haitchi, Hans Michael
68dadb29-305d-4236-884f-e9c93f4d78fe
Hoefler, Gerald
d0386835-9d48-4c6b-b0bb-4ce85a460a85
Klepetko, Walter
5d7505e9-d8a0-42cf-824e-a4dae8c1e2f0
Olschewski, Horst
5aa51ba9-ddff-420e-8b7d-2f030c7823bd
Olschewski, Andrea
30851e9c-364f-4837-a7b3-116a634f0da9
Kwapiszewska, Grazyna
82e3e30d-22fa-44eb-a21a-12eeae7bc5c7
Hoffmann, Julia
63ae071e-6886-40b3-a4f8-abf0c5c6573b
Marsh, Leigh M.
993ee686-f303-4994-9f49-14ae3fbdcc42
Pieper, Mario
39dd94fc-600d-4093-82fe-30ed6601812d
Stacher, Elvira
03071ea9-2c92-4a96-b645-c18a7d184675
Ghanim, Bahil
e19d471c-be9c-463a-81f3-885dea1fb44a
Kovacs, Gabor
703ce405-347a-4f27-b194-f59365ce053c
König, Peter
3cdc95dc-0345-4024-8241-5c1d14a76d1d
Wilkens, Heinrike
76701aa4-c627-46dc-a07e-5bfc9603c794
Haitchi, Hans Michael
68dadb29-305d-4236-884f-e9c93f4d78fe
Hoefler, Gerald
d0386835-9d48-4c6b-b0bb-4ce85a460a85
Klepetko, Walter
5d7505e9-d8a0-42cf-824e-a4dae8c1e2f0
Olschewski, Horst
5aa51ba9-ddff-420e-8b7d-2f030c7823bd
Olschewski, Andrea
30851e9c-364f-4837-a7b3-116a634f0da9
Kwapiszewska, Grazyna
82e3e30d-22fa-44eb-a21a-12eeae7bc5c7

Hoffmann, Julia, Marsh, Leigh M., Pieper, Mario, Stacher, Elvira, Ghanim, Bahil, Kovacs, Gabor, König, Peter, Wilkens, Heinrike, Haitchi, Hans Michael, Hoefler, Gerald, Klepetko, Walter, Olschewski, Horst, Olschewski, Andrea and Kwapiszewska, Grazyna (2015) Compartment-specific expression of collagens and their processing enzymes in intrapulmonary arteries of IPAH patients. American Journal of Physiology. Lung Cellular and Molecular Physiology, 308 (10), L1002-L1013. (doi:10.1152/ajplung.00383.2014). (PMID:25840998)

Record type: Article

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.

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More information

Accepted/In Press date: 26 March 2015
e-pub ahead of print date: 3 April 2015
Published date: 15 May 2015
Keywords: vascular remodeling, vascular fibrosis, laser microdissection, collagen xviii, endostatin
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 386151
URI: https://eprints.soton.ac.uk/id/eprint/386151
ISSN: 1040-0605
PURE UUID: 95331f5b-1101-4eb3-9acf-614d8dd0e417
ORCID for Hans Michael Haitchi: ORCID iD orcid.org/0000-0001-8603-302X

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Date deposited: 28 Jan 2016 14:23
Last modified: 06 Jun 2018 12:47

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Contributors

Author: Julia Hoffmann
Author: Leigh M. Marsh
Author: Mario Pieper
Author: Elvira Stacher
Author: Bahil Ghanim
Author: Gabor Kovacs
Author: Peter König
Author: Heinrike Wilkens
Author: Gerald Hoefler
Author: Walter Klepetko
Author: Horst Olschewski
Author: Andrea Olschewski
Author: Grazyna Kwapiszewska

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