| 1. |
- Egana, I, et al.
(författare)
-
Female mice lacking Pald1 exhibit endothelial cell apoptosis and emphysema
- 2017
-
Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1, s. 15453-
-
Tidskriftsartikel (refereegranskat)abstract
- Paladin (Pald1, mKIAA1274 or x99384) was identified in screens for vascular-specific genes and is a putative phosphatase. Paladin has also been proposed to be involved in various biological processes such as insulin signaling, innate immunity and neural crest migration. To determine the role of paladin we have now characterized the Pald1 knock-out mouse in a broad array of behavioral, physiological and biochemical tests. Here, we show that female, but not male, Pald1 heterozygous and homozygous knock-out mice display an emphysema-like histology with increased alveolar air spaces and impaired lung function with an obstructive phenotype. In contrast to many other tissues where Pald1 is restricted to the vascular compartment, Pald1 is expressed in both the epithelial and mesenchymal compartments of the postnatal lung. However, in Pald1 knock-out females, there is a specific increase in apoptosis and proliferation of endothelial cells, but not in non-endothelial cells. This results in a transient reduction of endothelial cells in the maturing lung. Our data suggests that Pald1 is required during lung vascular development and for normal function of the developing and adult lung in a sex-specific manner. To our knowledge, this is the first report of a sex-specific effect on endothelial cell apoptosis.
|
|
| 2. |
|
|
| 3. |
- Martinez-Corral, Ines, et al.
(författare)
-
Blockade of VEGF-C signaling inhibits lymphatic malformations driven by oncogenic PIK3CA mutation
- 2020
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- Lymphatic malformations (LMs) are debilitating vascular anomalies presenting with large cysts (macrocystic) or lesions that infiltrate tissues (microcystic). Cellular mechanisms underlying LM pathology are poorly understood. Here we show that the somatic PIK3CA(H1047R) mutation, resulting in constitutive activation of the p110 alpha PI3K, underlies both macrocystic and microcystic LMs in human. Using a mouse model of PIK3CA(H1047R)-driven LM, we demonstrate that both types of malformations arise due to lymphatic endothelial cell (LEC)-autonomous defects, with the developmental timing of p110 alpha activation determining the LM subtype. In the postnatal vasculature, PIK3CA(H1047R) promotes LEC migration and lymphatic hypersprouting, leading to microcystic LMs that grow progressively in a vascular endothelial growth factor C (VEGF-C)-dependent manner. Combined inhibition of VEGF-C and the PI3K downstream target mTOR using Rapamycin, but neither treatment alone, promotes regression of lesions. The best therapeutic outcome for LM is thus achieved by co-inhibition of the upstream VEGF-C/VEGFR3 and the downstream PI3K/mTOR pathways. Lymphatic malformation (LM) is a debilitating often incurable vascular disease. Using a mouse model of LM driven by a disease-causative PIK3CA mutation, the authors show that vascular growth is dependent on the upstream lymphangiogenic VEGF-C signalling, permitting effective therapeutic intervention.
|
|
| 4. |
- Niaudet, Colin, et al.
(författare)
-
Adgrf5 contributes to patterning of the endothelial deep layer in retina
- 2019
-
Ingår i: Angiogenesis. - : SPRINGER. - 0969-6970 .- 1573-7209. ; 22:4, s. 491-505
-
Tidskriftsartikel (refereegranskat)abstract
- Neovascularization of the inner retinal space is a major cause of vision loss. In retinal angiomatous proliferation (RAP) syndrome, newly formed vessels originate from the retinal plexus and invade the inner retinal space. However, the molecular pathways preventing subretinal vascularization remain largely unknown. In most murine models of RAP, pathological neo-vascularization occurs concomitantly with the development of the retinal vasculature. Here, we demonstrate that disturbing the sequence of morphogenetic events that shape the three-layered retinal vascular network leads to subretinal vascularization. Sprouts emerging from the perivenous region after the first postnatal week extended toward the retinal space where they merged into the deep layer. The small GTPase Rac1 was required for the formation of these vascular extensions and the vascular inner plexus is formed coaxially to the overarching veins. The adhesion receptor Adgrf5 was highly expressed in the endothelium of the central nervous system, where it regulates blood-brain barrier formation. The vascular superficial plexus of Adgrf5 mutant mouse retinae exhibited an increased vascular density in the perivenous areas with increased projections toward the inner plexus where they subsequently created hyper-dense endothelial cells (EC) clusters. Disturbing the perivenous pool of EC thus significantly altered the inner plexus formation. These abnormalities culminated in transient vascular protrusions in the inner retinal space. Taken together, these results reveal a previously unobserved vascular morphogenetic defect in Adgrf5 knockout mice, implicating a role for ADGRF5 in the initiation of subretinal vascularization. Our findings also illustrate how vein-derived EC shape the inner retinal layer formation and could control the appearance of angiomatous malformations.
|
|
| 5. |
- Petkova, Milena
(författare)
-
Cell-autonomous and paracrine mechanisms underlying Pik3ca-driven vascular malformations
- 2024
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Vascular malformation is a benign overgrowth of blood or lymphatic vessels leading to life-threatening consequences for affected patients. Activating mutations in the TIE2 receptor cause the majority of venous malformations (VMs), while somatic activating mutations in PIK3CA, leading to the overactivation of the PI3K-AKT pathway, cause both VMs and lymphatic malformations (LMs). Although molecular inhibitors targeting the PI3K-AKT-mTOR pathway, such as rapamycin, have shown beneficial effects, they are not curative. This thesis aimed to explore the endothelial cell-autonomous and paracrine mechanisms underlying Pik3ca-driven pathological vascular growth to identify a rationale for improved and curative therapies for vascular malformations.In Paper I, we reported that one of the most common causative mutations, PIK3CAH1047R, gives rise to two distinct LM subtypes known as macrocystic and microcystic LM in humans. Using a transgenic mouse model with temporally controlled LEC-specific activation of Pik3caH1047R, we found that the growth of microcystic LM is dependent on both the upstream pro-lymphangiogenic VEGF-C-VEGFR3 and the downstream AKT-mTOR signalling. Combination treatment targeting both signalling pathways led to effective inhibition of lesion growth in mice, suggesting a novel therapeutic approach for LM patients. In Paper II, we explored further the endothelial cell-autonomous and paracrine mechanisms underlying microcystic LM growth in mice. Using single-cell RNA sequencing, we identified a new immune-interacting subtype of dermal lymphatic capillary endothelial cells, termed iLECs. We showed that in Pik3ca mutant mice, iLECs produce factors that recruit pro-lymphangiogenic VEGF-C-producing macrophages. Macrophage depletion, inhibition of their recruitment, and anti-inflammatory COX-2 treatment resulted in decreased lymphatic growth, indicating a critical role of paracrine signalling between iLECs and immune cells in the pathogenesis of microcystic LM. In Paper III, we described distinct lymphatic vessel responses to oncogenic PI3K activation in different organs. We observed that while lymphatic vessels in the skin form microcystic LM through vessel sprouting, in certain other organs, they form large cysts reminiscent of macrocystic LM. Finally, we used mice with a BEC-specific activation of Pik3caH1047R to compare disease mechanisms in VM to those in LM in Paper II and to focus further on the former in Paper IV.
|
|
| 6. |
- Petkova, Milena, et al.
(författare)
-
Immune-interacting lymphatic endothelial subtype at capillary terminals drives lymphatic malformation
- 2023
-
Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 220:4
-
Tidskriftsartikel (refereegranskat)abstract
- Oncogenic mutations in PIK3CA, encoding p110α-PI3K, are a common cause of venous and lymphatic malformations. Vessel type–specific disease pathogenesis is poorly understood, hampering development of efficient therapies. Here, we reveal a new immune-interacting subtype of Ptx3-positive dermal lymphatic capillary endothelial cells (iLECs) that recruit pro-lymphangiogenic macrophages to promote progressive lymphatic overgrowth. Mouse model of Pik3caH1047R-driven vascular malformations showed that proliferation was induced in both venous and lymphatic ECs but sustained selectively in LECs of advanced lesions. Single-cell transcriptomics identified the iLEC population, residing at lymphatic capillary terminals of normal vasculature, that was expanded in Pik3caH1047R mice. Expression of pro-inflammatory genes, including monocyte/macrophage chemokine Ccl2, in Pik3caH1047R-iLECs was associated with recruitment of VEGF-C–producing macrophages. Macrophage depletion, CCL2 blockade, or anti-inflammatory COX-2 inhibition limited Pik3caH1047R-driven lymphangiogenesis. Thus, targeting the paracrine crosstalk involving iLECs and macrophages provides a new therapeutic opportunity for lymphatic malformations. Identification of iLECs further indicates that peripheral lymphatic vessels not only respond to but also actively orchestrate inflammatory processes.
|
|
| 7. |
- Petkova, Milena, et al.
(författare)
-
Lymphatic malformations : mechanistic insights and evolving therapeutic frontiers
- 2024
-
Ingår i: Journal of Clinical Investigation. - : American Society For Clinical Investigation. - 0021-9738 .- 1558-8238. ; 134:6
-
Tidskriftsartikel (refereegranskat)abstract
- The lymphatic vascular system is gaining recognition for its multifaceted role and broad pathological significance. Once perceived as a mere conduit for interstitial fluid and immune cell transport, recent research has unveiled its active involvement in critical physiological processes and common diseases, including inflammation, autoimmune diseases, and atherosclerosis. Consequently, abnormal development or functionality of lymphatic vessels can result in serious health complications. Here, we discuss lymphatic malformations (LMs), which are localized lesions that manifest as fluid -filled cysts or extensive infiltrative lymphatic vessel overgrowth, often associated with debilitating, even life -threatening, consequences. Genetic causes of LMs have been uncovered, and several promising drug -based therapies are currently under investigation and will be discussed.
|
|
| 8. |
|
|
