Endothelial alpha-parvin controls integrity of developing vasculature and is required for maintenance of cell-cell junctions.
BACKGROUND
Angiogenesis and vessel integrity depend on the adhesion of endothelial cells (ECs) to the extracellular matrix and to adjacent ECs. The focal adhesion protein α-parvin (α-pv) is essential for vascular development. However, the role of α-pv in ECs in vivo is not known.


OBJECTIVE
To determine the function of α-pv in ECs during vascular development in vivo and the underlying mechanisms.


RESULTS
We deleted the α-pv gene specifically in ECs of mice to study its role in angiogenesis and vascular development. Here, we show that endothelial-specific deletion of α-pv in mice results in late embryonic lethality associated with hemorrhages and reduced vascular density. Postnatal-induced EC-specific deletion of α-pv leads to retinal hypovascularization because of reduced vessel sprouting and excessive vessel regression. In the absence of α-pv, blood vessels display impaired VE-cadherin junction morphology. In vitro, α-pv-deficient ECs show reduced stable adherens junctions, decreased monolayer formation, and impaired motility, associated with reduced formation of integrin-mediated cell-extracellular matrix adhesion structures and an altered actin cytoskeleton.


CONCLUSIONS
Endothelial α-pv is essential for vessel sprouting and for vessel stability.
From the Walter-Brendel-Centre of Experimental Medicine (A.F., B.P., J.K., U.P., E.M.) and Department of Pharmacy (S.Z.), Ludwig-Maximilians University Munich, Munich, Germany; Institute of Anatomy and Vascular Biology, WWU-Münster, Münster, Germany (A.A.T., J.S., H.-J.S.); Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Swammerdam Institute for Life Sciences, Amsterdam, The Netherlands (S.H.); Department of Surgery, School of Medicine and Hospital Clinic de Barcelona (IDIBAPS), University of Barcelona, Barcelona, Spain (R.P.C.-M.); and Vascular Biology Laboratory, London Research Institute-Cancer Research United Kingdom, London, United Kingdom (H.G.).
Alessia
A
Fraccaroli
From the Walter-Brendel-Centre of Experimental Medicine (A.F., B.P., J.K., U.P., E.M.) and Department of Pharmacy (S.Z.), Ludwig-Maximilians University Munich, Munich, Germany; Institute of Anatomy and Vascular Biology, WWU-Münster, Münster, Germany (A.A.T., J.S., H.-J.S.); Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Swammerdam Institute for Life Sciences, Amsterdam, The Netherlands (S.H.); Department of Surgery, School of Medicine and Hospital Clinic de Barcelona (IDIBAPS), University of Barcelona, Barcelona, Spain (R.P.C.-M.); and Vascular Biology Laboratory, London Research Institute-Cancer Research United Kingdom, London, United Kingdom (H.G.).
Bettina
B
Pitter
From the Walter-Brendel-Centre of Experimental Medicine (A.F., B.P., J.K., U.P., E.M.) and Department of Pharmacy (S.Z.), Ludwig-Maximilians University Munich, Munich, Germany; Institute of Anatomy and Vascular Biology, WWU-Münster, Münster, Germany (A.A.T., J.S., H.-J.S.); Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Swammerdam Institute for Life Sciences, Amsterdam, The Netherlands (S.H.); Department of Surgery, School of Medicine and Hospital Clinic de Barcelona (IDIBAPS), University of Barcelona, Barcelona, Spain (R.P.C.-M.); and Vascular Biology Laboratory, London Research Institute-Cancer Research United Kingdom, London, United Kingdom (H.G.).
Abdallah Abu
AA
Taha
From the Walter-Brendel-Centre of Experimental Medicine (A.F., B.P., J.K., U.P., E.M.) and Department of Pharmacy (S.Z.), Ludwig-Maximilians University Munich, Munich, Germany; Institute of Anatomy and Vascular Biology, WWU-Münster, Münster, Germany (A.A.T., J.S., H.-J.S.); Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Swammerdam Institute for Life Sciences, Amsterdam, The Netherlands (S.H.); Department of Surgery, School of Medicine and Hospital Clinic de Barcelona (IDIBAPS), University of Barcelona, Barcelona, Spain (R.P.C.-M.); and Vascular Biology Laboratory, London Research Institute-Cancer Research United Kingdom, London, United Kingdom (H.G.).
Jochen
J
Seebach
From the Walter-Brendel-Centre of Experimental Medicine (A.F., B.P., J.K., U.P., E.M.) and Department of Pharmacy (S.Z.), Ludwig-Maximilians University Munich, Munich, Germany; Institute of Anatomy and Vascular Biology, WWU-Münster, Münster, Germany (A.A.T., J.S., H.-J.S.); Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Swammerdam Institute for Life Sciences, Amsterdam, The Netherlands (S.H.); Department of Surgery, School of Medicine and Hospital Clinic de Barcelona (IDIBAPS), University of Barcelona, Barcelona, Spain (R.P.C.-M.); and Vascular Biology Laboratory, London Research Institute-Cancer Research United Kingdom, London, United Kingdom (H.G.).
Stephan
S
Huveneers
From the Walter-Brendel-Centre of Experimental Medicine (A.F., B.P., J.K., U.P., E.M.) and Department of Pharmacy (S.Z.), Ludwig-Maximilians University Munich, Munich, Germany; Institute of Anatomy and Vascular Biology, WWU-Münster, Münster, Germany (A.A.T., J.S., H.-J.S.); Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Swammerdam Institute for Life Sciences, Amsterdam, The Netherlands (S.H.); Department of Surgery, School of Medicine and Hospital Clinic de Barcelona (IDIBAPS), University of Barcelona, Barcelona, Spain (R.P.C.-M.); and Vascular Biology Laboratory, London Research Institute-Cancer Research United Kingdom, London, United Kingdom (H.G.).
Julian
J
Kirsch
From the Walter-Brendel-Centre of Experimental Medicine (A.F., B.P., J.K., U.P., E.M.) and Department of Pharmacy (S.Z.), Ludwig-Maximilians University Munich, Munich, Germany; Institute of Anatomy and Vascular Biology, WWU-Münster, Münster, Germany (A.A.T., J.S., H.-J.S.); Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Swammerdam Institute for Life Sciences, Amsterdam, The Netherlands (S.H.); Department of Surgery, School of Medicine and Hospital Clinic de Barcelona (IDIBAPS), University of Barcelona, Barcelona, Spain (R.P.C.-M.); and Vascular Biology Laboratory, London Research Institute-Cancer Research United Kingdom, London, United Kingdom (H.G.).
Ricardo P
RP
Casaroli-Marano
From the Walter-Brendel-Centre of Experimental Medicine (A.F., B.P., J.K., U.P., E.M.) and Department of Pharmacy (S.Z.), Ludwig-Maximilians University Munich, Munich, Germany; Institute of Anatomy and Vascular Biology, WWU-Münster, Münster, Germany (A.A.T., J.S., H.-J.S.); Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Swammerdam Institute for Life Sciences, Amsterdam, The Netherlands (S.H.); Department of Surgery, School of Medicine and Hospital Clinic de Barcelona (IDIBAPS), University of Barcelona, Barcelona, Spain (R.P.C.-M.); and Vascular Biology Laboratory, London Research Institute-Cancer Research United Kingdom, London, United Kingdom (H.G.).
Stefan
S
Zahler
From the Walter-Brendel-Centre of Experimental Medicine (A.F., B.P., J.K., U.P., E.M.) and Department of Pharmacy (S.Z.), Ludwig-Maximilians University Munich, Munich, Germany; Institute of Anatomy and Vascular Biology, WWU-Münster, Münster, Germany (A.A.T., J.S., H.-J.S.); Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Swammerdam Institute for Life Sciences, Amsterdam, The Netherlands (S.H.); Department of Surgery, School of Medicine and Hospital Clinic de Barcelona (IDIBAPS), University of Barcelona, Barcelona, Spain (R.P.C.-M.); and Vascular Biology Laboratory, London Research Institute-Cancer Research United Kingdom, London, United Kingdom (H.G.).
Ulrich
U
Pohl
From the Walter-Brendel-Centre of Experimental Medicine (A.F., B.P., J.K., U.P., E.M.) and Department of Pharmacy (S.Z.), Ludwig-Maximilians University Munich, Munich, Germany; Institute of Anatomy and Vascular Biology, WWU-Münster, Münster, Germany (A.A.T., J.S., H.-J.S.); Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Swammerdam Institute for Life Sciences, Amsterdam, The Netherlands (S.H.); Department of Surgery, School of Medicine and Hospital Clinic de Barcelona (IDIBAPS), University of Barcelona, Barcelona, Spain (R.P.C.-M.); and Vascular Biology Laboratory, London Research Institute-Cancer Research United Kingdom, London, United Kingdom (H.G.).
Holger
H
Gerhardt
From the Walter-Brendel-Centre of Experimental Medicine (A.F., B.P., J.K., U.P., E.M.) and Department of Pharmacy (S.Z.), Ludwig-Maximilians University Munich, Munich, Germany; Institute of Anatomy and Vascular Biology, WWU-Münster, Münster, Germany (A.A.T., J.S., H.-J.S.); Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Swammerdam Institute for Life Sciences, Amsterdam, The Netherlands (S.H.); Department of Surgery, School of Medicine and Hospital Clinic de Barcelona (IDIBAPS), University of Barcelona, Barcelona, Spain (R.P.C.-M.); and Vascular Biology Laboratory, London Research Institute-Cancer Research United Kingdom, London, United Kingdom (H.G.).
Hans-J
HJ
Schnittler
From the Walter-Brendel-Centre of Experimental Medicine (A.F., B.P., J.K., U.P., E.M.) and Department of Pharmacy (S.Z.), Ludwig-Maximilians University Munich, Munich, Germany; Institute of Anatomy and Vascular Biology, WWU-Münster, Münster, Germany (A.A.T., J.S., H.-J.S.); Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Swammerdam Institute for Life Sciences, Amsterdam, The Netherlands (S.H.); Department of Surgery, School of Medicine and Hospital Clinic de Barcelona (IDIBAPS), University of Barcelona, Barcelona, Spain (R.P.C.-M.); and Vascular Biology Laboratory, London Research Institute-Cancer Research United Kingdom, London, United Kingdom (H.G.). Eloi.Montanez@med.uni-muenchen.de.
Eloi
E
Montanez
D022005:Adherens Junctions / Q000502:physiology / Q000648:ultrastructure*; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D001808:Blood Vessels / Q000196:embryology* / Q000254:growth & development; D015820:Cadherins / Q000032:analysis; D002465:Cell Movement; D048430:Cell Shape; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000648:ultrastructure; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000502:physiology* / Q000648:ultrastructure; D005109:Extracellular Matrix / Q000648:ultrastructure; D005260:Female; D005804:Genes, Lethal; D061307:Human Umbilical Vein Endothelial Cells; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology*; D011554:Pseudopodia / Q000502:physiology / Q000648:ultrastructure; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D012171:Retinal Vessels / Q000473:pathology; D000099152:Cadherin 5; D000096985:Calponins
D015703:Antigens, CD; D015820:Cadherins; D008840:Microfilament Proteins; D034741:RNA, Small Interfering; D000099152:Cadherin 5; C486590:PARVA protein, human; D000096985:Calponins; C519774:Parva protein, mouse
adherens junctions; angiogenesis; blood vessels; cell adhesion molecules; growth and development