Abnormal Vessel Formation in the Choroid of Mice Lacking Tissue Inhibitor of Metalloprotease-3

Janßen, Andreas; Hoellenriegel, Julia; Fogarasi, Marton; Schrewe, Heinrich; Seeliger, Mathias W.; Tamm, Ernst R.; Ohlmann, Andreas; May, Christian Albrecht; Weber, Bernhard H. F.; Stöhr, Heidi

doi:10.1167/iovs.07-1444

Cited by 66 publications

(53 citation statements)

References 37 publications

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“…Furthermore, recent reports suggest that Timp3-deficient mice have kidney fibrosis. 31,42,43 We therefore investigated the microvasculature of normal Timp3 2/2 kidneys, the response of the kidney microvasculature to acute ischemia reperfusion injury (IRI), and the function of pericytes in these vascular responses. Adult Timp3 2/2 mice were smaller than littermate controls but had normal renal function and no albuminuria ( Table 2).…”

Section: Timp3 Mutant Mice Have a Kidney Microvascular Phenotypementioning

confidence: 99%

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Pericyte TIMP3 and ADAMTS1 Modulate Vascular Stability after Kidney Injury

Schrimpf

Xin

Campanholle

et al. 2012

Journal of the American Society of Nephrology

175

191

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Kidney pericytes are progenitors of scar-forming interstitial myofibroblasts that appear after injury. The function of kidney pericytes as microvascular cells and how these cells detach from peritubular capillaries and migrate to the interstitial space, however, are poorly understood. Here, we used an unbiased approach to identify genes in kidney pericytes relevant to detachment and differentiation in response to injury in vivo, with a particular focus on genes regulating proteolytic activity and angiogenesis. Kidney pericytes rapidly activated expression of a disintegrin and metalloprotease with thrombospondin motifs-1 (ADAMTS1) and downregulated its inhibitor, tissue inhibitor of metalloproteinase 3 (TIMP3) in response to injury. Similarly to brain pericytes, kidney pericytes bound to and stabilized capillary tube networks in three-dimensional gels and inhibited metalloproteolytic activity and angiogenic signaling in endothelial cells. In contrast, myofibroblasts did not have these vascular stabilizing functions despite their derivation from kidney pericytes. Pericyte-derived TIMP3 stabilized and ADAMTS1 destabilized the capillary tubular networks. Furthermore, mice deficient in Timp3 had a spontaneous microvascular phenotype in the kidney resulting from overactivated pericytes and were more susceptible to injury-stimulated microvascular rarefaction with an exuberant fibrotic response. Taken together, these data support functions for kidney pericytes in microvascular stability, highlight central roles for regulators of extracellular proteolytic activity in capillary homoeostasis, and identify ADAMTS1 as a marker of activation of kidney pericytes.

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Section: Timp3 Mutant Mice Have a Kidney Microvascular Phenotypementioning

confidence: 99%

“…1,9,23 Timp3 2/2 gene-targeted homozygous mice and littermate controls were generated as previously described 31,43 and maintained on the C57BL6 background.…”

Section: Animalsmentioning

confidence: 99%

Pericyte TIMP3 and ADAMTS1 Modulate Vascular Stability after Kidney Injury

Schrimpf

Xin

Campanholle

et al. 2012

Journal of the American Society of Nephrology

175

191

View full text Add to dashboard Cite

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“…In humans, mutations in the TIMP-3 gene cause Sorsby's fundus dystrophy (Weber et al 1994), an autosomal dominant disorder characterized by abnormal Bruch's membrane thickening, choroidal neovascularization, retinal degeneration, and loss of vision usually by middle age (Sorsby and Mason 1949). Mice lacking TIMP-3 in their eyes develop abnormal choroidal vessels (Janssen et al 2008) The goal of this study was to characterize the distribution of TIMP-3 in human vascular tissues, using tissue microarrays (TMAs) containing samples taken from 100 subjects undergoing autopsy (Halushka et al in press). We hypothesized that TIMP-3 would be differentially expressed in the various tissues on these TMAs.…”

mentioning

confidence: 99%

Tissue Inhibitor of Matrix Metalloproteinase-3 Levels in the Extracellular Matrix of Lung, Kidney, and Eye Increase With Age

Macgregor

Eberhart

Fraig

et al. 2008

J Histochem Cytochem.

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S U M M A R Y Tissue inhibitor of matrix metalloproteinase-3 (TIMP-3) is an important regulator of matrix metalloproteinase activity in many types of disease, including atherosclerosis, neoplasia, and inflammatory conditions. Among TIMPs, TIMP-3 uniquely binds the extracellular matrix (ECM). We performed IHC staining on 17 tissue microarrays containing .1500 samples to determine the location of ECM TIMP-3 staining in a variety of predominantly vascular tissues. We found a unique pattern of TIMP-3 staining in the ECM of renal arterioles, small pulmonary vessels and parenchyma, and Bruch's membrane in the retina. There was no staining in larger caliber arteries including coronary and internal mammary arteries. TIMP-3 protein accumulation was found to be an age-dependent phenomenon, with staining appearing in all three tissues in early adulthood and becoming more robust among the elderly. These findings may help to explain the late onset of the TIMP-3-associated ocular diseases Sorsby fundus dystrophy and age-related macular degeneration and suggest a similar phenomenon could be at work in other age-related conditions.

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“…In the eye TIMP-3 is closely related to Bruch's membrane and regulates angiogenesis (Janssen et al, 2008). Analysis of micromatrix demonstrated that out of investigated metalloproteinases and its inhibitors: MMP1, MMP2, MMP11, MMP14, MMP25, TIMP1, TIMP2, TIMP3 and TIMP4 which were present in pericytes, only TIMIP3 mRNA may play role in impairment of microcirculation in diabetic retinopathy (Barth et al, 2007).…”

Section: Tissue Inhibitor Of Matrix Metalloproteinase 3 (Timp-3)mentioning

confidence: 99%

Immunological Risk Factors for the Development and Progression of Diabetic Retinopathy

Zorena¹,

Raczyńska²,

Raczyńska³

2012

Diabetic Retinopathy

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Abnormal Vessel Formation in the Choroid of Mice Lacking Tissue Inhibitor of Metalloprotease-3

Abstract: These findings suggest that the distinct choroidal phenotype in mice lacking TIMP3 may be the result of a local disruption of extracellular matrix and angiogenic homeostasis, and they support an important role of TIMP3 in the regulation of choroidal vascularization.

Cited by 66 publications

References 37 publications

Pericyte TIMP3 and ADAMTS1 Modulate Vascular Stability after Kidney Injury

Pericyte TIMP3 and ADAMTS1 Modulate Vascular Stability after Kidney Injury

Tissue Inhibitor of Matrix Metalloproteinase-3 Levels in the Extracellular Matrix of Lung, Kidney, and Eye Increase With Age

Immunological Risk Factors for the Development and Progression of Diabetic Retinopathy

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