Lecticans in Vascular Remodeling of the Pulmonary and Fetal Circulation : Implications for Children with End-Stage Heart Disease
van der Have, Oscar LU
(2025)
In Lund University, Faculty of Medicine Doctoral Dissertation Series
- Abstract
- Introduction: Elevated pulmonary vascular resistance (PVR) is observed in both physiological and pathological states. Pulmonary hypertension (PH) is a condition associated with significant morbidity and mortality in neonates and children and curative pharmacotherapy is lacking in most cases. In utero, a high PVR allows for blood to bypass the lungs through the open ductus arteriosus (DA). Vascular remodeling in PH development and DA closure is characterized by abundant deposition of extracellular matrix, including proteoglycans. The proteoglycan sub-family lecticans have remained largely un-studied in these settings. In children with end-stage heart disease, high PVR complicates clinical management and has been associated with poor outcome... (More)
- Introduction: Elevated pulmonary vascular resistance (PVR) is observed in both physiological and pathological states. Pulmonary hypertension (PH) is a condition associated with significant morbidity and mortality in neonates and children and curative pharmacotherapy is lacking in most cases. In utero, a high PVR allows for blood to bypass the lungs through the open ductus arteriosus (DA). Vascular remodeling in PH development and DA closure is characterized by abundant deposition of extracellular matrix, including proteoglycans. The proteoglycan sub-family lecticans have remained largely un-studied in these settings. In children with end-stage heart disease, high PVR complicates clinical management and has been associated with poor outcome following pediatric heart transplantation (pHTx).
Methods: The accumulation, spatial distribution and temporal regulation of the two lecticans aggrecan and versican was investigated in human PH and DA specimens using a combination of synchrotron-based phase-contrast microcomputed tomography and histology, immunostaining, mRNA in situ hybridization and spatial proteomics. In addition, we investigated clinical practice in Sweden and internationally in children with PH listed for pHTx, through a survey- and registry-based approach.
Results: In PH, lecticans were shown to be expressed by vascular smooth muscle cells and endothelial cells and accumulated early in lesion development. Multiple different isoforms of versican were present and degraded by members of the ADAMTS protease family, and versican was found at elevated concentrations in PH patient plasma. Within the pulmonary vascular tree, aggrecan and versican preferentially accumulated at, or proximally to, sites of elevated PVR. Versican and aggrecan were furthermore shown to accumulate at high levels during the early phases of anatomical remodeling of the closing DA, with progressive degradation by ADAMTS proteases at later stages of remodeling. Surveying international practice patterns for patients with PH and end-stage heart disease revealed significant heterogeneity in hemodynamic evaluation, treatment with pulmonary vasodilators and cut-offs for precluding patients for isolated for pHTx. Within the Swedish cohort of children listed for pHTx, children with elevated PVR did not fare worse off post-pHTx but very few patients with a fixed PVRi above 6 WU·m2 had been listed and transplanted.
Conclusions: In summary, early lectican accumulation in pulmonary and fetal vascular remodeling appears vital and turnover of lecticans by ADAMTS proteases is an intriguing target for future pharmacological therapies. Clinical practice in children with PH and heart disease is heterogenous but does not appear to have influenced post-pHTx outcomes in Sweden. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/332469c2-6064-4695-ae16-e8805df16f72
- author
- van der Have, Oscar
LU
- supervisor
- opponent
-
- Associate professor, MD, PhD Andersen, Asger, Department of Clinical Medicine, Aarhus University, Denmark; Department of Cardiology, Aarhus University Hospital, Denmark
- organization
- publishing date
- 2025
- type
- Thesis
- publication status
- published
- subject
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- issue
- 2025:48
- pages
- 95 pages
- publisher
- Lund University, Faculty of Medicine
- defense location
- Belfragesalen, BMC D15, Klinikgatan 32 i Lund
- defense date
- 2025-05-08 08:30:00
- ISSN
- 1652-8220
- ISBN
- 978-91-8021-701-9
- project
- Lecticans in Vascular Remodeling of the Pulmonary and Fetal Circulation
- language
- English
- LU publication?
- yes
- id
- 332469c2-6064-4695-ae16-e8805df16f72
- date added to LUP
- 2025-04-01 12:32:02
- date last changed
- 2025-06-02 13:48:36
@phdthesis{332469c2-6064-4695-ae16-e8805df16f72,
abstract = {{Introduction: Elevated pulmonary vascular resistance (PVR) is observed in both physiological and pathological states. Pulmonary hypertension (PH) is a condition associated with significant morbidity and mortality in neonates and children and curative pharmacotherapy is lacking in most cases. In utero, a high PVR allows for blood to bypass the lungs through the open ductus arteriosus (DA). Vascular remodeling in PH development and DA closure is characterized by abundant deposition of extracellular matrix, including proteoglycans. The proteoglycan sub-family lecticans have remained largely un-studied in these settings. In children with end-stage heart disease, high PVR complicates clinical management and has been associated with poor outcome following pediatric heart transplantation (pHTx).<br/><br/>Methods: The accumulation, spatial distribution and temporal regulation of the two lecticans aggrecan and versican was investigated in human PH and DA specimens using a combination of synchrotron-based phase-contrast microcomputed tomography and histology, immunostaining, mRNA in situ hybridization and spatial proteomics. In addition, we investigated clinical practice in Sweden and internationally in children with PH listed for pHTx, through a survey- and registry-based approach. <br/><br/>Results: In PH, lecticans were shown to be expressed by vascular smooth muscle cells and endothelial cells and accumulated early in lesion development. Multiple different isoforms of versican were present and degraded by members of the ADAMTS protease family, and versican was found at elevated concentrations in PH patient plasma. Within the pulmonary vascular tree, aggrecan and versican preferentially accumulated at, or proximally to, sites of elevated PVR. Versican and aggrecan were furthermore shown to accumulate at high levels during the early phases of anatomical remodeling of the closing DA, with progressive degradation by ADAMTS proteases at later stages of remodeling. Surveying international practice patterns for patients with PH and end-stage heart disease revealed significant heterogeneity in hemodynamic evaluation, treatment with pulmonary vasodilators and cut-offs for precluding patients for isolated for pHTx. Within the Swedish cohort of children listed for pHTx, children with elevated PVR did not fare worse off post-pHTx but very few patients with a fixed PVRi above 6 WU·m2 had been listed and transplanted. <br/><br/>Conclusions: In summary, early lectican accumulation in pulmonary and fetal vascular remodeling appears vital and turnover of lecticans by ADAMTS proteases is an intriguing target for future pharmacological therapies. Clinical practice in children with PH and heart disease is heterogenous but does not appear to have influenced post-pHTx outcomes in Sweden.}},
author = {{van der Have, Oscar}},
isbn = {{978-91-8021-701-9}},
issn = {{1652-8220}},
language = {{eng}},
number = {{2025:48}},
publisher = {{Lund University, Faculty of Medicine}},
school = {{Lund University}},
series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
title = {{Lecticans in Vascular Remodeling of the Pulmonary and Fetal Circulation : Implications for Children with End-Stage Heart Disease}},
url = {{https://lup.lub.lu.se/search/files/212799356/Oscar_van_der_Have_-_WEBB.pdf}},
year = {{2025}},
}