Smooth muscle cell deletion of low-density lipoprotein receptor-related protein 1 augments angiotensin II-induced superior mesenteric arterial and ascending aortic aneurysms.
OBJECTIVE
Low-density lipoprotein receptor-related protein 1 (LRP1), a multifunctional protein involved in endocytosis and cell signaling pathways, leads to several vascular pathologies when deleted in vascular smooth muscle cells (SMCs). The purpose of this study was to determine whether LRP1 deletion in SMCs influenced angiotensin II-induced arterial pathologies.


RESULTS
LRP1 protein abundance was equivalent in selected arterial regions, but SMC-specific LRP1 depletion had no effect on abdominal and ascending aortic diameters in young mice. To determine the effects of LRP1 deficiency on angiotensin II vascular responses, SMC-specific LRP1 (smLRP1(+/+)) and smLRP1-deficient (smLRP1(-/-)) mice were infused with saline, angiotensin II, or norepinephrine. Several smLRP(-/-) mice died of superior mesenteric arterial (SMA) rupture during angiotensin II infusion. In surviving mice, angiotensin II profoundly augmented SMA dilation in smLRP1(-/-) mice. SMA dilation was blood pressure dependent as demonstrated by a similar response during norepinephrine infusion. SMA dilation was also associated with profound macrophage accumulation, but minimal elastin fragmentation. Angiotensin II infusion led to no significant differences in abdominal aorta diameters between smLRP1(+/+) and smLRP1(-/-) mice. In contrast, ascending aortic dilation was exacerbated markedly in angiotensin II-infused smLRP1(-/-) mice, but norepinephrine had no significant effect on either aortic region. Ascending aortas of smLRP1(-/-) mice infused with angiotensin II had minimal macrophage accumulation but significantly increased elastin fragmentation and mRNA abundance of several LRP1 ligands including MMP-2 (matrix metalloproteinase-2) and uPA (urokinase plasminogen activator).


CONCLUSIONS
smLRP1 deficiency had no effect on angiotensin II-induced abdominal aortic aneurysm formation. Conversely, angiotensin II infusion in smLRP1(-/-) mice exacerbated SMA and ascending aorta dilation. Dilation in these 2 regions had differential association with blood pressure and divergent pathological characteristics.
From the Saha Cardiovascular Research Center (F.M.D., D.L.R., A.B., D.A.H., C.M.H., B.K.F., A.D.), Department of Pediatrics (B.K.F.), Department of Pharmacology and Nutritional Sciences (L.A.C.), University of Kentucky, Lexington; and Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore (D.K.S., S.C.M.).
Frank M
FM
Davis
From the Saha Cardiovascular Research Center (F.M.D., D.L.R., A.B., D.A.H., C.M.H., B.K.F., A.D.), Department of Pediatrics (B.K.F.), Department of Pharmacology and Nutritional Sciences (L.A.C.), University of Kentucky, Lexington; and Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore (D.K.S., S.C.M.).
Debra L
DL
Rateri
From the Saha Cardiovascular Research Center (F.M.D., D.L.R., A.B., D.A.H., C.M.H., B.K.F., A.D.), Department of Pediatrics (B.K.F.), Department of Pharmacology and Nutritional Sciences (L.A.C.), University of Kentucky, Lexington; and Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore (D.K.S., S.C.M.).
Anju
A
Balakrishnan
From the Saha Cardiovascular Research Center (F.M.D., D.L.R., A.B., D.A.H., C.M.H., B.K.F., A.D.), Department of Pediatrics (B.K.F.), Department of Pharmacology and Nutritional Sciences (L.A.C.), University of Kentucky, Lexington; and Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore (D.K.S., S.C.M.).
Deborah A
DA
Howatt
From the Saha Cardiovascular Research Center (F.M.D., D.L.R., A.B., D.A.H., C.M.H., B.K.F., A.D.), Department of Pediatrics (B.K.F.), Department of Pharmacology and Nutritional Sciences (L.A.C.), University of Kentucky, Lexington; and Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore (D.K.S., S.C.M.).
Dudley K
DK
Strickland
From the Saha Cardiovascular Research Center (F.M.D., D.L.R., A.B., D.A.H., C.M.H., B.K.F., A.D.), Department of Pediatrics (B.K.F.), Department of Pharmacology and Nutritional Sciences (L.A.C.), University of Kentucky, Lexington; and Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore (D.K.S., S.C.M.).
Selen C
SC
Muratoglu
From the Saha Cardiovascular Research Center (F.M.D., D.L.R., A.B., D.A.H., C.M.H., B.K.F., A.D.), Department of Pediatrics (B.K.F.), Department of Pharmacology and Nutritional Sciences (L.A.C.), University of Kentucky, Lexington; and Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore (D.K.S., S.C.M.).
Christopher M
CM
Haggerty
From the Saha Cardiovascular Research Center (F.M.D., D.L.R., A.B., D.A.H., C.M.H., B.K.F., A.D.), Department of Pediatrics (B.K.F.), Department of Pharmacology and Nutritional Sciences (L.A.C.), University of Kentucky, Lexington; and Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore (D.K.S., S.C.M.).
Brandon K
BK
Fornwalt
From the Saha Cardiovascular Research Center (F.M.D., D.L.R., A.B., D.A.H., C.M.H., B.K.F., A.D.), Department of Pediatrics (B.K.F.), Department of Pharmacology and Nutritional Sciences (L.A.C.), University of Kentucky, Lexington; and Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore (D.K.S., S.C.M.).
Lisa A
LA
Cassis
From the Saha Cardiovascular Research Center (F.M.D., D.L.R., A.B., D.A.H., C.M.H., B.K.F., A.D.), Department of Pediatrics (B.K.F.), Department of Pharmacology and Nutritional Sciences (L.A.C.), University of Kentucky, Lexington; and Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore (D.K.S., S.C.M.). Alan.Daugherty@uky.edu.
Alan
A
Daugherty
D000783:Aneurysm / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000804:Angiotensin II; D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism / Q000473:pathology; D001014:Aortic Aneurysm / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D062186:Arterial Pressure; D002478:Cells, Cultured; D004108:Dilatation, Pathologic; D004195:Disease Models, Animal; D004549:Elastin / Q000378:metabolism; D017353:Gene Deletion; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008264:Macrophages / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D017538:Mesenteric Artery, Superior / Q000378:metabolism / Q000473:pathology; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D009638:Norepinephrine; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism
D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D012333:RNA, Messenger; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; D000804:Angiotensin II; D004549:Elastin; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D009638:Norepinephrine
LRP1 protein, mouse; angiotensin II; aortic aneurysm