scholarly journals Impaired VEGF Signaling in Lungs with Hypoplastic Esophageal Atresia and Effects on Branching Morphogenesis

2016 ◽  
Vol 39 (1) ◽  
pp. 385-394 ◽  
Author(s):  
Xiaomei Liu ◽  
Caixia Liu ◽  
Tie Ma ◽  
Yisheng Jiao ◽  
Jianing Miao ◽  
...  
Keyword(s):  
Esophageal Atresia ◽  
Branching Morphogenesis ◽  
Lung Growth ◽  
Compensatory Response ◽  
Pregnant Rats ◽  
Vegf Signaling ◽  
Vegf Pathway ◽  
Tract Disease ◽  
Endothelial Growth Factor

Background/Aims: Patients with esophageal atresia (EA) and tracheoesophageal fistula (TEF) often suffer chronic respiratory tract disease. We previously reported that primary lung maldevelopment caused by deficient branching of embryonal airways in experimental EA-TEF was induced by Adriamycin. In this study, we investigated the Vascular endothelial growth factor (VEGF) pathway in the developing lung in an EA-TEF rat model. We further analyzed the effect of recombinant VEGF treatment in vitro on branching morphogenesis of embryo lungs in experimental EA-TEF. Methods: Pregnant rats received either Adriamycin or vehicle on E7, E8 and E9. Lungs were recovered at E15, E18 and E21. Expression of VEGF and receptors (Flk-1 and Flt-1) were assessed by quantitative PCR, immunohistochemistry and immunoblotting. E13 lungs were cultured for 72 hours with 50 ng/mL of recombinant rat VEGF in serum-free medium. The rates of increase in bud count and airway contour were evaluated. Results: Our results showed a significant downregulation of VEGF during pseudoglandular and canalicular stages. In contrast, there were significantly higher levels of the Flt-1 receptor in the canalicular stage, which may represent a compensatory response to decreased VEGF. However, both variables returned to normal levels at the saccular stage. Exogenous VEGF treatment enhanced hypoplastic lung growth, evidenced by the increase in bud count and airway contour. Conclusions: A VEGF signaling defect possibly plays an important role in defective embryonic airway branching. Additionally, VEGF treatment may accelerate lung growth in EA-TEF lungs.

scholarly journals Recent Advances and Future Prospects in Immune Checkpoint (ICI)-Based Combination Therapy for Advanced HCC

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1949
Author(s):  
Yawen Dong ◽  
Jeffrey Sum Lung Wong ◽  
Ryohichi Sugimura ◽  
Ka-On Lam ◽  
Bryan Li ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Advanced Hcc ◽  
Oncogenic Pathways ◽  
Vegf Pathway ◽  
And Function ◽  
Endothelial Growth Factor

Advanced, unresectable hepatocellular carcinoma has a dismal outcome. Multiple immune checkpoint inhibitors (ICIs) targeting the programmed-cell death 1 pathway (PD-1/L1) have been approved for the treatment of advanced HCC. However, outcomes remain undesirable and unpredictable on a patient-to-patient basis. The combination of anti-PD-1/L1 with alternative agents, chiefly cytotoxic T-lymphocyte antigen-4 (CTLA-4) ICIs or agents targeting other oncogenic pathways such as the vascular endothelial growth factor (VEGF) pathway and the c-MET pathway, has, in addition to the benefit of directly targeting alterative oncogenic pathways, in vitro evidence of synergism through altering the genomic and function signatures of T cells and expression of immune checkpoints. Several trials have been completed or are underway evaluating such combinations. Finally, studies utilizing transcriptomics and organoids are underway to establish biomarkers to predict ICI response. This review aims to discuss the biological rationale and clinical advances in ICI-based combinations in HCCs, as well as the progress and prospects of the search for the aforementioned biomarkers in ICI treatment of HCC.

Abstract 215: Allogeneic MSCs Improve Endothelial Function in Patients with Dilated Cardiomyopathy via an SDF-1α-mediated Mechanism and the Suppression of Pathologic Cytokines

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Courtney Premer ◽  
Ivonne H Schulman ◽  
Wayne Balkan ◽  
Valeria Porras ◽  
Michael A Bellio ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Dilated Cardiomyopathy ◽  
Necrosis Factor Alpha ◽  
Allogeneic Mscs ◽  
Vegf Signaling ◽  
Factor Alpha ◽  
And Function ◽  
Endothelial Growth Factor

Endothelial dysfunction is central to the pathophysiology of heart failure, including dilated cardiomyopathy (DCM). Current drug therapies are unable to halt the progression of DCM, compelling the emergence of novel stem cell therapy approaches. Mesenchymal stem cells (MSCs) are pro-angiogenic, immunomodulatory, antifibrotic, and stimulate endogenous endothelial progenitor (EPC) proliferation and function, thus having the potential to ameliorate endothelial dysfunction. We demonstrated that patients with DCM who received allogeneic MSCs had a significant improvement in endothelial function 3-months post treatment, whereas patients who received autologous MSCs had no improvement. Therefore, we hypothesized that allogeneic MSCs preferentially improve endothelial function via a mechanism involving the suppression of pathologic levels of vascular endothelial growth factor (VEGF), stromal derived factor-1 alpha (SDF-1α), and tumor necrosis factor alpha (TNFα). Accordingly, patient serum VEGF and TNFα were measured at baseline and 3 months post MSC treatment. In vitro, MSC secretion of SDF-1α and TNFα was also measured. Our results show that patients with DCM had elevated levels of VEGF (n=21, 581.2±812.2 pg/mL) and TNFα (n=15, 22±9.4 pg/mL) at baseline, and that only allogeneic MSCs were able to restore these levels toward normal (VEGF: n=10, Δ-267.1±252.1, P=0.01; TNFα: n=8, Δ-7.1±3.1 pg/mL, P=0.0005). While there was no difference in TNFα secretion by autologous or allogeneic MSCs (0.01±0.14 vs. 0.4±0.6 pg/mL), autologous MSCs secreted significantly higher levels of SDF-1α compared to allogeneic MSCs (n=12, 79.3±16.7 vs. 14.2±9.4 pg/mL, P=0.0001). In vitro secreted SDF-1α and serum VEGF and TNFα levels correlated with EPC bioactivity (ΔSDF-1α to ΔEPC-CFUs, R=-0.9, P<0.0001; ΔVEGF to ΔEPC-CFUs, R=-0.7, P=0.001; ΔTNFα to ΔEPC-CFUs, R=-0.6, P=0.01). These findings reveal a novel mechanism by which allogeneic MSCs secrete physiologic levels of SDF-1α resulting in physiologic levels of VEGF signaling, reduced TNFα, increased EPC bioactivity, and improved endothelial function. These findings have important clinical and biological implications for the use of MSCs in patients with DCM.

scholarly journals Chondroitin sulfate proteoglycans are required for lung growth and morphogenesis in vitro

2003 ◽  
Vol 285 (6) ◽  
pp. L1323-L1336 ◽  
Author(s):  
John M. Shannon ◽  
Kathleen McCormick-Shannon ◽  
Michael S. Burhans ◽  
Xiaofei Shangguan ◽  
Kalpana Srivastava ◽  
...  
Keyword(s):  
Chondroitin Sulfate ◽  
Lung Development ◽  
Sodium Chlorate ◽  
Surfactant Protein ◽  
Branching Morphogenesis ◽  
Clara Cell ◽  
Normal Lung ◽  
Lung Growth ◽  
Isolated Lung

Proteoglycans (PGs) have been shown to play a key role in the development of many tissues. We have investigated the role of sulfated PGs in early rat lung development by treating cultured tissues with 30 mM sodium chlorate, a global inhibitor of PG sulfation. Chlorate treatment disrupted growth and branching of embryonic day 13 lung explants. Isolated lung epithelium (LgE) migrated toward and invaded lung mesenchyme (LgM), and chlorate irreversibly suppressed this response. Chlorate also inhibited migration of LgE toward beads soaked in FGF10. Chlorate severely decreased branching morphogenesis in tissue recombinants consisting of LgM plus either LgE or tracheal epithelium (TrE) and decreased expression of surfactant protein C gene ( SP-C). Chlorate also reduced bone morphogenetic protein-4 expression in cultured tips and recombinants but had no effect on the expression of clara cell 10-kDa protein ( CC10), sonic hedgehog ( Shh), FGF10, and FGF receptor 2IIIb. Chlorate reduced the growth of LgE in mesenchyme-free culture but did not affect SP-C expression. In contrast, chlorate inhibited both rudiment growth and the induction of SP-C in mesenchyme-free cultured TrE. Treatment of lung tips and tissue recombinants with chondroitinase ABC abolished branching morphogenesis. Chondroitinase also suppressed growth of TrE in mesenchyme-free culture. Chondroitinase treatment, however, had no effect on the induction of SP-C expression in any of these cultures. These results demonstrate the overall importance of sulfated PGs to normal lung development and demonstrate a dynamic role for chondroitin sulfate PGs in embryonic lung growth and morphogenesis.

scholarly journals Expression of Tumor-Derived Vascular Endothelial Growth Factor and Its Receptors Is Associated With Outcome in Early Squamous Cell Carcinoma of the Lung

2012 ◽  
Vol 30 (10) ◽  
pp. 1129-1136 ◽  
Author(s):  
María J. Pajares ◽  
Jackeline Agorreta ◽  
Marta Larrayoz ◽  
Aurélien Vesin ◽  
Teresa Ezponda ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Vascular Endothelial Growth Factor ◽  
Squamous Cell Carcinoma ◽  
Growth Factor ◽  
Vascular Endothelial ◽  
Vegf Signaling ◽  
Vegf Pathway ◽  
Cell Expression ◽  
Endothelial Growth Factor ◽  
Histologic Subtypes

PurposeAntiangiogenic therapies targeting the vascular endothelial growth factor (VEGF) pathway have yielded more modest clinical benefit to patients with non–small-cell lung cancer (NSCLC) than initially expected. Clinical data suggest a distinct biologic role of the VEGF pathway in the different histologic subtypes of lung cancer. To clarify the influence of histologic differentiation in the prognostic relevance of VEGF-mediated signaling in NSCLC, we performed a concomitant analysis of the expression of three key elements of the VEGF pathway in the earliest stages of the following two principal histologic subtypes: squamous cell carcinoma (SCC) and adenocarcinoma (ADC).Patients and MethodsWe evaluated tumor cell expression of VEGF, VEGF receptor (VEGFR) 1, and VEGFR2 using automatic immunostaining in a series of 298 patients with early-stage NSCLC recruited as part of the multicenter European Early Lung Cancer Detection Group project. A score measuring the VEGF signaling pathway was calculated by adding the tumor cell expression value of VEGF and its two receptors. The results were validated in two additional independent cohorts of patients with NSCLC.ResultsThe combination of high VEGF, VEGFR1, and VEGFR2 protein expression was associated with lower risk of disease progression in early SCC (univariate analysis, P = .008; multivariate analysis, hazard ratio, 0.62; 95% CI, 0.42 to 0.92; P = .02). The results were validated in two independent patient cohorts, confirming the favorable prognostic value of high VEGF signaling score in early lung SCC.ConclusionOur results clearly indicate that the combination of high expression of the three key elements in the VEGF pathway is associated with a good prognosis in patients with early SCC but not in patients with ADC.

scholarly journals Possible co-option of a VEGF-driven tubulogenesis program for biomineralization in echinoderms

2019 ◽  
Author(s):  
Miri Morgulis ◽  
Tsvia Gildor ◽  
Modi Roopin ◽  
Noa Sher ◽  
Assaf Malik ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Sea Urchin ◽  
Regulatory Networks ◽  
Critical Role ◽  
Vascular Endothelial ◽  
Upstream Gene ◽  
Vegf Signaling ◽  
Vegf Pathway ◽  
Endothelial Growth Factor

AbstractBiomineralization is the process in which living organisms use minerals to form hard structures that protect and support them. Biomineralization is believed to have evolved rapidly and independently in different phyla utilizing existing components used for other purposes. The mechanistic understanding of the regulatory networks that drive biomineralization and their evolution is far from clear. The sea urchin skeletogenesis is an excellent model system for studying both gene regulation and mineral uptake and deposition. The sea urchin calcite spicules are formed within a tubular cavity generated by the skeletogenic cells under the control the vascular endothelial growth factor (VEGF) signaling. The VEGF pathway controls tubulogenesis and vascularization across metazoans while its regulation of biomineralization was only observed in echinoderms. Despite the critical role of VEGF signaling in sea urchin spiculogenesis, the downstream program it activates was largely unknown. Here we study the cellular and molecular machinery activated by the VEGF pathway during sea urchin spiculogenesis and reveal multiple parallels to the regulation of tubulogenesis during vertebrate vascularization. Human VEGF rescues sea urchin VEGF knock-down; VEGF-dependent vesicle deposition plays a significant role in both systems and sea urchin VEGF signaling activates hundreds of genes including biomineralization and vascularization genes. Five upstream transcription factors and three signaling genes active in spiculogenesis are homologous to vertebrate factors that regulate vascularization. Overall, our findings suggest that sea urchin spiculogenesis and vertebrate vascularization diverged from a common ancestral tubulogenesis program, broadly adapted for vascularization and specifically co-opted for biomineralization in the echinoderm phylum.Significance statementThe sea urchin calcite spicules and vertebrate blood vessels are quite distinct in their function, yet both have a tubular structure and are controlled by the vascular endothelial growth factor (VEGF) pathway. Here we study the downstream program by which VEGF pathway drives sea urchin spiculogenesis and find remarkable similarities to the control of vertebrate vascularization. The similarities are observed both in the upstream gene regulatory network, in the downstream effector genes and the cellular processes that VEGF signaling controls at the site of the calcite spicule formation. We speculate that sea urchin spiculogenesis and vertebrate vascularization diverged from a common ancestral tubulogenesis program that was co-opted for biomineralization in the echinoderm phylum.

scholarly journals Endothelial Semaphorin 3fb regulates Vegf pathway-mediated angiogenic sprouting

2021 ◽  
Author(s):  
Charlene Watterston ◽  
Rami Halabi ◽  
Sarah McFarlane ◽  
Sarah J Childs
Keyword(s):  
Growth Factor ◽  
Critical Role ◽  
Developmental Time ◽  
Vegf Receptor ◽  
Growth Factor Signaling ◽  
Actin Assembly ◽  
Vegf Signaling ◽  
Vessel Growth ◽  
Vegf Pathway ◽  
Endothelial Growth Factor

Vessel growth integrates diverse extrinsic signals with intrinsic signaling cascades to coordinate cell migration and sprouting morphogenesis. The pro-angiogenic effects of Vascular Endothelial Growth Factor (VEGF) are carefully controlled during sprouting to generate an efficiently patterned vascular network. We identify crosstalk between VEGF signaling and that of the secreted ligand Semaphorin 3fb (Sema3fb), one of two zebrafish paralogs of mammalian Sema3F. The sema3fb gene is expressed by endothelial cells in actively sprouting vessels. Loss of sema3fb results in abnormally wide and stunted intersegmental vessel artery sprouts. Although the sprouts initiate at the correct developmental time, they have a reduced migration speed. These sprouts have persistent filopodia and abnormally spaced nuclei suggesting dysregulated control of actin assembly. sema3fb mutants show simultaneously higher expression of pro-angiogenic (VEGF receptor 2 (vegfr2) and delta-like 4 (dll4)) and anti-angiogenic (soluble VEGF receptor 1 (svegfr1)/ soluble Fms Related Receptor Tyrosine Kinase 1 (sflt1)) pathway components. We show increased phospho-ERK staining in migrating angioblasts, consistent with enhanced Vegf activity. Reducing Vegfr2 kinase activity in sema3fb mutants rescues angiogenic sprouting. Our data suggest that Sema3fb plays a critical role in promoting endothelial sprouting through modulating the VEGF signaling pathway, acting as an autocrine cue that modulates intrinsic growth factor signaling.

Abstract P613: The Effect of Metabolic Factors on Hypoxia-Induced sFlt-1 Secretion in Rat Placental Villi

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Ana C Palei ◽  
Frank T Spradley ◽  
Joey P Granger
Keyword(s):  
Trophoblast Invasion ◽  
Vascular Endothelial ◽  
Metabolic Factors ◽  
Maternal Circulation ◽  
Pregnant Rats ◽  
Hypoxic Conditions ◽  
Placental Villi ◽  
Endothelial Growth Factor ◽  
Placental Ischemia

Although the etiology of preeclampsia (PE) remains unclear, evidence indicates that impaired trophoblast invasion followed by placental ischemia/hypoxia promotes the release of placental anti-angiogenic factors, such as soluble fms-like tyrosine kinase-1 (sFlt-1), into the maternal circulation. sFlt-1 blocks the pro-angiogenic actions of vascular endothelial growth factor to elicit maternal endothelial dysfunction and ultimately hypertension. Obesity is a major risk factor for PE. In addition, increased circulating metabolic factors, such as leptin and insulin have been associated with PE. However, the mechanisms whereby obesity and its related metabolic factors increase the risk for the development of PE are unknown. The aim of this study was to evaluate whether chronic leptin or insulin exposure exacerbate hypoxia-induced sFlt-1 secretion from rat placental villi. In order to address this question, placental villous explants were isolated from placentas of normal pregnant rats (n=4, 3 placentas per rat) and pregnant rats treated with either leptin (0.5 mg/kg/min i.p.; n=3, 3 placentas per rat) or insulin (1.5 mU/kg/min s.c.) supplemented with 20% glucose in drinking water (n=3, 3 placentas per rat) from gestational day 14 to 19. Placental explants were then incubated for 48 h at 37 °C under normoxia (6% O2) or hypoxia (1% O2) and sFlt-1 secretion in cultured media was measured by ELISA. While hypoxia significantly enhanced sFlt-1 release of explants from normal pregnant rats compared with normoxia (3224±224 vs 4251±236 pg/mg; P<0.05), explants from chronic hyperleptinemic (3197±178 vs. 3762±317 pg/mg) or euglycemic hyperinsulinemic (4066±186 vs. 4251±213 pg/mg) pregnant rats secreted similar sFlt-1 levels under normoxic and hypoxic conditions, respectively. Additionally, chronic leptin or insulin treatments did not exacerbate the effect of hypoxia on sFlt-1 release. In conclusion, our in vitro studies with placental villi from chronic hyperleptinemic or euglycemic hyperinsulinemic pregnant rats showed no exacerbation of hypoxia-induced sFlt-1 secretion.

scholarly journals Inhibition of VEGF- and NO-dependent angiogenesis does not impair liver regeneration

2010 ◽  
Vol 298 (5) ◽  
pp. R1279-R1287 ◽  
Author(s):  
U. Shergill ◽  
A. Das ◽  
D. Langer ◽  
RS. Adluri ◽  
N. Maulik ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Fetal Liver ◽  
Vegf Receptor ◽  
Vegf Signaling ◽  
Endothelial Growth Factor ◽  
Nos Isoforms ◽  
Endothelial Nitric Oxide

Angiogenesis occurs through a convergence of diverse signaling mechanisms with prominent pathways that include autocrine effects of endothelial nitric oxide (NO) synthase (eNOS)-derived NO and vascular endothelial growth factor (VEGF). However, the redundant and distinct roles of NO and VEGF in angiogenesis remain incompletely defined. Here, we use the partial hepatectomy model in mice genetically deficient in eNOS to ascertain the influence of eNOS-derived NO on the angiogenesis that accompanies liver regeneration. While sinusoidal endothelial cell (SEC) eNOS promotes angiogenesis in vitro, surprisingly the absence of eNOS did not influence the angiogenesis that occurs after partial hepatectomy in vivo. While this observation could not be attributed to induction of alternate NOS isoforms, it was associated with induction of VEGF signaling as evidenced by enhanced levels of VEGF ligand in regenerating livers from mice genetically deficient in eNOS. However, surprisingly, mice that were genetically heterozygous for deficiency in the VEGF receptor, fetal liver kinase-1, also maintained unimpaired capacity for liver regeneration. In summary, inhibition of VEGF- and NO-dependent angiogenesis does not impair liver regeneration, indicating signaling redundancies that allow liver regeneration to continue in the absence of this canonical vascular pathway.

scholarly journals Excess soluble vascular endothelial growth factor receptor-1 in amniotic fluid impairs lung growth in rats: linking preeclampsia with bronchopulmonary dysplasia

2012 ◽  
Vol 302 (1) ◽  
pp. L36-L46 ◽  
Author(s):  
Jen-Ruey Tang ◽  
S. Ananth Karumanchi ◽  
Gregory Seedorf ◽  
Neil Markham ◽  
Steven H. Abman
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Amniotic Fluid ◽  
Bronchopulmonary Dysplasia ◽  
Growth Factor Receptor ◽  
In Utero ◽  
Vascular Endothelial ◽  
Lung Growth ◽  
Vegf Signaling ◽  
Endothelial Growth Factor

Epidemiological studies have shown that maternal preeclampsia (PE) increases the risk of bronchopulmonary dysplasia (BPD), but the underlying mechanism is unknown. Soluble vascular endothelial growth factor receptor-1 (soluble VEGFR1, known as soluble fms-like tyrosine kinase 1, or sFlt-1), an endogenous antagonist of vascular endothelial growth factor (VEGF), is markedly elevated in amniotic fluid and maternal blood in PE. Therefore, we hypothesized that antenatal exposure to excess sFlt-1 disrupts lung development through impaired VEGF signaling in utero, providing a mechanistic link between PE and BPD. To determine whether increased sFlt-1 in amniotic fluid is sufficient to cause sustained abnormalities of lung structure during infancy, sFlt-1 or saline was injected into amniotic sacs of pregnant Sprague-Dawley rats at 20 days of gestation (term, 22 days). After birth, pups were observed through 14 days of age for study. We found that intra-amniotic sFlt-1 treatment decreased alveolar number, reduced pulmonary vessel density, and caused right and left ventricular hypertrophy in 14-day-old rats. In addition, intra-amniotic sFlt-1 treatment suppressed activation of lung VEGF receptor-2 and increased apoptosis in endothelial and mesenchymal cells in the newborn lung. We conclude that exposure to excess sFlt-1 in amniotic fluid during late gestation causes sustained reductions in alveolarization and pulmonary vascular growth during infancy, accompanied by biventricular hypertrophy suggesting pulmonary and systemic hypertension. We speculate that impaired VEGF signaling in utero due to exposure of high amniotic fluid levels of sFlt-1 in PE disrupts lung growth and contributes to the increased risk of BPD in infants born to mothers with PE.

scholarly journals Gelatinolytic activity of autocrine matrix metalloproteinase-9 leads to endothelial de-arrangement in Moyamoya disease

2018 ◽  
Vol 38 (11) ◽  
pp. 1940-1953 ◽  
Author(s):  
Kinga G Blecharz-Lang ◽  
Vincent Prinz ◽  
Małgorzata Burek ◽  
Dietmar Frey ◽  
Tobias Schenkel ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Moyamoya Disease ◽  
Matrix Metalloproteinase 9 ◽  
Vegf Signaling ◽  
Specific Effects ◽  
Vitro Model ◽  
Novel Therapeutic Strategies ◽  
Endothelial Growth Factor ◽  
Metalloproteinase 9

Moyamoya disease (MMD) is a rare steno-occlusive cerebrovascular disorder. Mechanisms driving the formation of aberrant MMD vessels remain elusive. We collected serum and vessel specimens from MMD and atherosclerotic cerebrovascular disease (ACVD) patients serving as controls due to the same hypoxic stimulus but substantial differences in terms of vascular features. Based on patient material and an in vitro model mimicking ACVD and MMD conditions, matrix metalloproteinase-9 (MMP-9) and vascular-endothelial growth factor (VEGF) were tested for their potential involvement in cerebrovascular disintegration. While serum concentration of both molecules did not significantly differ in both patient groups, excessive collagenase activity and lowered collagen IV protein amount in MMD vessels pointed to a focal MMP-9 activity at the affected vessel sites. We observed overexpressed and autocrinely secreted MMP-9 and VEGF along with disturbances of EC–matrix interactions in MMD but not ACVD serum-treated cEND cells. These seemingly brain-specific effects were partially attenuated by VEGF signaling inhibition suggesting its role in the MMD etiology. In conclusion, our findings support the understanding of the high incidence of hemorrhagic and ischemic events in MMD and provide the basis for novel therapeutic strategies stopping or slowing the development of fragile cerebrovasculature or micro-bleeds characterizing the disease.

Sign in / Sign up

Export Citation Format

Share Document