Tissue Inhibitor of Metalloproteinase 1 Influences Vascular Adaptations to Chronic Alterations in Blood Flow

Abstract

Remodeling of the skeletal muscle microvasculature involves the coordinated actions of matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitor of metalloproteinases (TIMPs). We hypothesized that the loss of TIMP1 would enhance both ischemia and flow-induced vascular remodeling by increasing MMP activity. TIMP1 deficient (Timp1 ) and wild-type (WT) C57BL/6 mice underwent unilateral femoral artery (FA) ligation or were treated with prazosin, an alpha-1 adrenergic receptor antagonist, in order to investigate vascular remodeling to altered flow. Under basal conditions, Timp1 mice had reduced microvascular content as compared to WT mice. Furthermore, vascular remodeling was impaired in Timp1 mice. Timp1 mice displayed reduced blood flow recovery in response to FA ligation and no arteriogenic response to prazosin treatment. Timp1 mice failed to undergo angiogenesis in response to ischemia or prazosin, despite maintaining the capacity to increase VEGF-A and eNOS mRNA. Vascular permeability was increased in muscles of Timp1 mice in response to both prazosin treatment and FA ligation, but this was not accompanied by greater MMP activity. This study highlights a previously undescribed integral role for TIMP1 in both vascular network maturation and adaptations to ischemia or alterations in flow. J. Cell. Physiol. 232: 831-841, 2017. © 2016 Wiley Periodicals, Inc.

Endothelial Cell-Derived Extracellular Vesicles Mitigate Radiation-Induced Hematopoietic Injury

“…This finding is consistent with a previously published report that EVs from human umbilical vein ECs (HUVECs) contain high levels of TIMP-1 (35). Interestingly, mice that are deficient in TIMP-1 display aberrant microvascular networks, deranged vascular integrity, and diminished vascular remodeling following ischemia (36). Conversely, increased levels of TIMP-1 is associated with poorer prognosis in colorectal cancer with increased liver metastasis (37) and also promoted angiogenesis in a model of lung adenocarcinoma (38).…”

The impact of skeletal muscle contraction on CD146+Lin− pericytes

“…Baseline Timp1 gene expression is also positively correlated with posttraining strength gains in healthy older adults (16). Although TIMP1 is an inhibitor of matrix metalloproteinases and negative regulator of ECM turnover (6), it can also control vascular remodeling similar to FGF-2 and angiogenin (31,48,51). A recent study by Mandel et al (31) reported significant deficiencies in microvascular content as well as lack of prazosin-mediated arteriogenesis in TIMP1 deficient (Timp1 Ϫ/Ϫ ) mice.…”

High‐fat diet pre‐conditioning improves microvascular remodelling during regeneration of ischaemic mouse skeletal muscle

“…Hindlimb and/or paw blood flow was assessed prior to and immediately post‐ligation surgery (day 0), then subsequently on days 4, 7 and 14 by laser Doppler imaging (Perimed), with mice under light isoflurane anaesthesia and positioned on a warming pad. Relative blood flow was expressed as a perfusion ratio of the ligated limb (paw) and the corresponding region in the contralateral non‐ligated leg . At 4 or 14 days post‐ligation, mice were killed while under isoflurane inhalation anaesthesia and muscles were excised from both ligated and non‐ligated legs.…”