Regeneration of the Endothelium in Vascular Injury

Abstract

The endothelium mediates relaxations (dilatations) of the underlying vascular smooth muscle cells. The endothelium-dependent relaxations are due to the release of non-prostanoid vasodilator substances. The best characterized endothelium-derived relaxing factor (EDRF) is nitric oxide (NO). The endothelial cells also release substances (endothelium-derived hyperpolarizing factor, EDHF) that cause hyperpolarization of the cell membrane of the underlying vascular smooth muscle. The release of EDRF from the endothelium can be mediated by both pertussis toxin-sensitive G(i) (alpha(2)-adrenergic activation, serotonin, thrombin) and insensitive G(q) (adenosine diphosphate, bradykinin) coupling proteins. The ability of the endothelial cell to release relaxing factors can be upregulated by impregnation with estrogens, exercise and antioxidants, and down-regulated by oxidative stress and increased presence of oxidized LDL. Following injury or apoptotic death, the endothelium regenerates. However, in regenerated endothelial cells, there is an early selective loss of the pertussis-toxin sensitive mechanisms of EDRF-release. Functional studies suggest that abnormal handling of LDL because of increased oxidative stress play a key role in this selective loss. Genomic analysis demonstrates the emergence of fatty acid binding protein-A (A-FBP) and metalloproteinase-7 (MMP7) in regenerated endothelial cells. The reduced release of NO resulting from the endothelial dysfunction in regenerated areas creates a locus minoris resistentiae which favors the occurrence of vasospasm and thrombosis as well as the initiation of atherosclerosis.

S-Nitrosothiols and theS-Nitrosoproteome of the Cardiovascular System

“…Vascular injury and ischemic heart disease Pathological remodeling of atherosclerotic blood vessels following vascular injury may be attenuated through the effects of NO on promoting vasodilation, inhibiting platelet activation, and limiting vascular smooth muscle cell proliferation (140). For example, the administration of NO donor pharmacotherapy to patients for 6 months following coronary balloon angioplasty is associated with an increase in the luminal diameter of the treated atherosclerotic blood vessels (78).…”

In Endothelial Cells, the Activation or Stimulation of Soluble Guanylyl Cyclase Induces the Nitric Oxide Production by a Mechanism Dependent of Nitric Oxide Synthase Activation

“…The vascular endothelium has an important protective role against cardiovascular disease, by release endothelium factor, which modulates vascular tonus, inflammation, and coagulation and the release of nitric oxide (NO) has a central role in this protection [1,2]. NO induces vasodilation by different mechanisms in order to decrease the cytoplasmic calcium concentration [Ca 2+ ] in vascular smooth muscle cells [3].…”

A-FABP and Oxidative Stress Underlie the Impairment of Endothelium-Dependent Relaxations to Serotonin and the Intima-Medial Thickening in the Porcine Coronary Artery with Regenerated Endothelium

“…Its effect on the platelets is to further amplify aggregation by potentiating the response to other inducers of platelet aggregation. 1,2 In most blood vessels, if the smooth muscle cells are exposed to serotonin, vasoconstriction occurs following activation of 5-HT2A and 5-HT1B/1D receptors. 3 However, in some arteries, the monoamine possesses vasodilator effects because it activates endothelial 5-HT 1D receptors on the endothelial cells.…”

“…8−11 Regenerated endothelial cells are dysfunctional because of loss of function of these G i proteins (Figure 1). 1,9,12 Therefore serotonin, released by activated platelets, in regions lined with such dysfunctional endothelial cells will cause contraction of the underlying vascular smooth muscle, rather than activating a protective response, hence promoting vasospasm, platelet aggregation, coagulation and local inflammation. 1,9,12−14 Primary cultures derived from regenerated porcine coronary arterial endothelial cells exhibit a different genomic profile compared to those derived from native endothelium of the same hearts.…”