Role of platelet-derived growth factor in vascular  remodeling during pulmonary hypertension in the ovine fetus

Platelet-derived growth factor (PDGF) is a potent smooth muscle cell mitogen that may contribute to smooth muscle hyperplasia during the development of chronic pulmonary hypertension (PH). We studied changes in PDGFα- and β-receptor and ligand expression in lambs with chronic intrauterine PH induced by partial ligation of the ductus arteriosus (DA) at gestational age 124–128 days (term = 147 days). Western blot analysis performed on whole lung homogenates from PH animals after 8 days of DA ligation showed a twofold increase in PDGFα- and β-receptor proteins compared with age-matched controls ( P < 0.05). Lung PDGF-A and -B mRNA expression did not differ between PH and control animals. We treated PH animals with NX1975, an aptamer that selectively inhibits PDGF-B, by infusion into the left pulmonary artery for 7 days after DA ligation. NX1975 reduced the development of muscular thickening of small pulmonary arteries by 47% ( P < 0.05) and right ventricular hypertrophy (RVH) by 66% ( P < 0.02). Lung PDGFα- and β-receptor expression is increased in perinatal PH, and NX1975 reduces the increase in wall thickness of small pulmonary arteries and RVH in this model. We speculate that PDGF signaling contributes to structural vascular remodeling in perinatal PH and that selective PDGF inhibition may provide a novel therapeutic strategy for the treatment of chronic PH.

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The Role of JAK/STAT Molecular Pathway in Vascular Remodeling Associated with Pulmonary Hypertension

International Journal of Molecular Sciences ◽

10.3390/ijms22094980 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4980

Author(s):

Inés Roger ◽

Javier Milara ◽

Paula Montero ◽

Julio Cortijo

Keyword(s):

Pulmonary Hypertension ◽

Smooth Muscle ◽

Pulmonary Artery ◽

Vascular Remodeling ◽

Pulmonary Arteries ◽

Clinical Manifestations ◽

Different Types ◽

Artery Remodeling ◽

Stat Pathway ◽

Pulmonary Artery Remodeling

Pulmonary hypertension is defined as a group of diseases characterized by a progressive increase in pulmonary vascular resistance (PVR), which leads to right ventricular failure and premature death. There are multiple clinical manifestations that can be grouped into five different types. Pulmonary artery remodeling is a common feature in pulmonary hypertension (PH) characterized by endothelial dysfunction and smooth muscle pulmonary artery cell proliferation. The current treatments for PH are limited to vasodilatory agents that do not stop the progression of the disease. Therefore, there is a need for new agents that inhibit pulmonary artery remodeling targeting the main genetic, molecular, and cellular processes involved in PH. Chronic inflammation contributes to pulmonary artery remodeling and PH, among other vascular disorders, and many inflammatory mediators signal through the JAK/STAT pathway. Recent evidence indicates that the JAK/STAT pathway is overactivated in the pulmonary arteries of patients with PH of different types. In addition, different profibrotic cytokines such as IL-6, IL-13, and IL-11 and growth factors such as PDGF, VEGF, and TGFβ1 are activators of the JAK/STAT pathway and inducers of pulmonary remodeling, thus participating in the development of PH. The understanding of the participation and modulation of the JAK/STAT pathway in PH could be an attractive strategy for developing future treatments. There have been no studies to date focused on the JAK/STAT pathway and PH. In this review, we focus on the analysis of the expression and distribution of different JAK/STAT isoforms in the pulmonary arteries of patients with different types of PH. Furthermore, molecular canonical and noncanonical JAK/STAT pathway transactivation will be discussed in the context of vascular remodeling and PH. The consequences of JAK/STAT activation for endothelial cells and pulmonary artery smooth muscle cells’ proliferation, migration, senescence, and transformation into mesenchymal/myofibroblast cells will be described and discussed, together with different promising drugs targeting the JAK/STAT pathway in vitro and in vivo.

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A Dual Inhibitor of Platelet-Derived Growth Factor β-Receptor and Src Kinase Activity Potently Interferes With Motogenic and Mitogenic Responses to PDGF in Vascular Smooth Muscle Cells

Circulation Research ◽

10.1161/01.res.85.1.12 ◽

1999 ◽

Vol 85 (1) ◽

pp. 12-22 ◽

Cited By ~ 73

Author(s):

Johannes Waltenberger ◽

Andrea Uecker ◽

Jens Kroll ◽

Hedwig Frank ◽

Ulrike Mayr ◽

...

Keyword(s):

Smooth Muscle ◽

Growth Factor ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Kinase Activity ◽

Muscle Cells ◽

Platelet Derived Growth Factor ◽

Dual Inhibitor ◽

Β Receptor

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Perspectives on endothelial-to-mesenchymal transition: potential contribution to vascular remodeling in chronic pulmonary hypertension

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00378.2006 ◽

2007 ◽

Vol 293 (1) ◽

pp. L1-L8 ◽

Cited By ~ 202

Author(s):

Enrique Arciniegas ◽

Maria G. Frid ◽

Ivor S. Douglas ◽

Kurt R. Stenmark

Keyword(s):

Pulmonary Hypertension ◽

Smooth Muscle ◽

Vascular Remodeling ◽

Serine Proteases ◽

Structural Changes ◽

Transforming Growth Factor ◽

Pulmonary Arteries ◽

Potential Contribution ◽

Mesenchymal Transition ◽

Endothelial Mesenchymal Transition

All forms of pulmonary hypertension are characterized by structural changes in pulmonary arteries. Increased numbers of cells expressing α-smooth muscle (α-SM) actin is a nearly universal finding in the remodeled artery. Traditionally, it was assumed that resident smooth muscle cells were the exclusive source of these newly appearing α-SM actin-expressing cells. However, rapidly emerging experimental evidence suggests other, alternative cellular sources of these cells. One possibility is that endothelial cells can transition into mesenchymal cells expressing α-SM actin and that this process contributes to the accumulation of SM-like cells in vascular pathologies. We review the evidence that endothelial-mesenchymal transition is an important contributor to cardiac and vascular development as well as to pathophysiological vascular remodeling. Recent work has provided evidence for the role of transforming growth factor-β, Wnt, and Notch signaling in this process. The potential roles of matrix metalloproteinases and serine proteases are also discussed. Importantly, endothelial-mesenchymal transition may be reversible. Thus insights into the mechanisms controlling endothelial-mesenchymal transition are relevant to vascular remodeling and are important as we consider new therapies aimed at reversing pulmonary vascular remodeling.

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Upregulation of ET-1 and its receptors and remodeling in small pulmonary veins under hypoxic conditions

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2001.280.6.l1104 ◽

2001 ◽

Vol 280 (6) ◽

pp. L1104-L1114 ◽

Cited By ~ 30

Author(s):

Hideki Takahashi ◽

Sanae Soma ◽

Masashi Muramatsu ◽

Masahiko Oka ◽

Yoshinosuke Fukuchi

Keyword(s):

Pulmonary Hypertension ◽

Smooth Muscle ◽

Vascular Remodeling ◽

Smooth Muscle Actin ◽

Pulmonary Veins ◽

Pulmonary Arteries ◽

Immunohistochemical Method ◽

Muscle Actin ◽

Converting Enzyme ◽

Hypoxic Conditions

Pulmonary veins show greater sensitivity to endothelin (ET)-1-induced vasoconstriction than pulmonary arteries, and remodeling was observed in pulmonary veins under hypoxic conditions. We examined, using an immunohistochemical method, the expression of Big ET-1, ET-converting enzyme (ECE), and ETA and ETB receptors in rat pulmonary veins under normoxic and hypoxic conditions. In control rats, Big ET-1 and ECE were coexpressed in the intima and media of the pulmonary veins, with an even distribution along the axial pathway. ETA and ETB receptors were expressed in the pulmonary veins, with a predominant distribution in the proximal segments. The expression of Big ET-1 was more abundant in the pulmonary veins than in the pulmonary arteries. After exposure to hypoxia for 7 or 14 days, the expression of Big ET-1, ECE, and ET receptors increased in small pulmonary veins. Increases in the medial thickness, wall thickness, and immunoreactivity for α-smooth muscle actin were also observed in the small pulmonary veins under hypoxic conditions. The upregulation of ET-1 and ET receptors in the small pulmonary veins is associated with vascular remodeling, which may lead to the development of hypoxic pulmonary hypertension.

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