Denis deBlois

Bio: Denis deBlois is an academic researcher from Université de Montréal. The author has contributed to research in topics: Neointima & Agonist. The author has an hindex of 24, co-authored 26 publications receiving 2672 citations. Previous affiliations of Denis deBlois include University of Washington & Laval University.

The Intima: Soil for Atherosclerosis and Restenosis

Abstract: Thirty years ago, John French wrote a seminal review describing the unique properties of the arterial intima.1 His major point was that the smooth muscle cells of the intima have a unique morphology (Fig 1⇓). French also pointed out that intimal formation appeared during normal development and aging as well as in the response of arteries to almost any imaginable injury, including atherosclerosis. Figure 1. Top left, Histology of intima vs media. Coronary artery is from an adult patient with idiopathic dilated cardiomyopathy. In the absence of atherosclerosis, there remains diffuse intimal hyperplasia. The intima is several cell layers thick and composed of smooth muscle cells and is separated from the distinct media by the internal elastic lamina (arrows) (hematoxylin and eosin, original magnification ×200). Top right, Advanced atherosclerosis of the left circumflex coronary artery. This lesion was treated by percutaneous balloon angioplasty 23 days before the patient’s death. Note the complex nature of the lesion with a distinct fibrous cap (FC), intimal hyperplasia (IHP), intramural hemorrhage (H), and a necrotic core (NC) composed of inflammatory cells and accumulated lipid (hematoxylin and eosin, original magnification ×100). Bottom left, Myxomatous tissue. Directional coronary atherectomy specimen from a restenotic lesion shows stellate-shaped smooth muscle cells. Smooth muscle cells with this appearance are often regarded as evidence of proliferation. Note the homogeneity of these cells and the absence of inflammatory and endothelial cells in this region (hematoxylin and eosin, original magnification ×200). Bottom right, Directional coronary atherectomy specimen from a primary lesion. Again, note the presence of stellate-shaped smooth muscle cells but a denser connective tissue matrix (hematoxylin and eosin, original magnification ×200). This article attempts to update French’s review. We will discuss the developmental origins of the intima and suggest that the arterial intima is a distinct tissue with a long and …

Smooth Muscle Apoptosis During Vascular Regression in Spontaneously Hypertensive Rats

Abstract: We previously reported that apoptosis is increased m smooth muscle cells cultured from the aorta of spontaneously hypertensive rats versus normotenslve controls. As an mtttal m viva exploration, we now exammed smooth muscle cell apoptosis regulation during the regression of vascular hypertrophy m the thoracic aorta media of spontaneously hypertensive rats receiving the antihypertensive drug enalapnl (30 mg kg-' d-'), losartan (30 mg kg-' d-'), mfedipme (35 mg kg-' d-l), hydralazme (40 mg kg-' d-'), propranolol(50 mg kg-' d-'), or hydrochlo- rothiazide (75 mg kg-' d-') for 1 to 4 weeks starting at 10 to 11 weeks of age Three criteria were used to evaluate smooth muscle cell apoptosis (1) ohgonucleosomal fragmentation of the extracted aortm DNA, (2) reduction in aortic DNA content, and (3) depletion of smooth muscle cells m the arterial media Arterial DNA synthesis was evaluated by (3H)thymidme mcorporation m viva After 4 weeks of treatment, systohc blood pressure was reduced stgmficantly by >42% wtth losartan, enalapnl, and hy- dralazme, and by 23% with mfedipme, versus control values of 22025 mm Hg. However, these agents affected vascular growth and apoptosis differently Losartan, enalapnl, and mfedipme stimulated smooth muscle cell apoptosrs threefold to fivefold be- fore there was a significant reduction m DNA synthesis (>25%), vascular mass (>19%), or vascular DNA content (>38%), and these treatments markedly reduced (by 38% to 50%) medial cell number as measured at 4 weeks by the three-dimensional disector method Losartan and mfedipme stimulated smooth muscle cell apoptosis before reducing blood pressure In contrast, hydralazme did not affect vascular mass, apoptosis, or DNA synthesis, al- though blood pressure was lowered Propranolol or hydrochlo- rothiazlde failed to affect hypertension or vascular growth Thus, smooth muscle cell apoptosls represents a novel therapeutic target for the control of hypertensive vessel remodeling m response to therapeutic agents (Hypertension. 1997;29(part 2):340-349.)

Studies on the induction of pharmacological responses to des-Arg9-bradykinin in vitro and in vivo.

Abstract: 1 The mechanisms by which agents modulate the induction of kinin B1-receptors were investigated by studying the effects of kinins in vitro, by use of the rabbit isolated aorta, and in vivo by measuring the blood pressure of anaesthetized rabbits. 2 The contractile response of the rabbit isolated aorta to kinins increased in a time-dependent manner in vitro. This effect was abolished by continuous exposure to the protein synthesis inhibitor cycloheximide (71 microM). 3 Several substances were found to increase specifically the rate of sensitization to des-Arg9-bradykinin (des-Arg9-Bk), when applied continuously in vitro to tissues isolated from normal animals: bacterial lipopolysaccharide (LPS; 1 micrograms ml-1), muramyl-dipeptide (MDP; 2 micrograms ml-1), phorbol myristate acetate (PMA; 320 nM), epidermal growth factor (EGF; 100 ng ml-1) and endothelial cell growth factor (150 micrograms ml-1). 4 The protease inhibitors phenylmethylsulphonyl fluoride and aprotinin, a non-adjuvant isomer of MDP, rabbit purified leukocyte interferon, fibroblast growth factor and the chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) did not have this effect. 5. It has been demonstrated that LPS induces B1-receptors in rabbits enabling des-Arg9-Bk to act as a hypotensive agent. In these experiments neutropenia induced by nitrogen mustard, did not prevent the in vivo effect of LPS. MDP (300 micrograms) and PMA (100 micrograms) were also found to induce a state of responsiveness to des-Arg9-Bk in vivo. FMLP (1 mg i.v.) induced a temporary decrease in blood neutrophil counts but had no effect on the induction of responses to des-Arg9-Bk. 6. The development of responses mediated by the B,-receptor in the two experimental systems seems to be unrelated to the activation of neutrophil leukocytes, but may be related to the activation of tissue macrophages. Approximately 3% of cultured adherent cells derived from rabbit aorta strips following protease digestion were stained for non-specific esterase, supporting such a possibility.

Effect of glucocorticoids, monokines and growth factors on the spontaneously developing responses of the rabbit isolated aorta to des-Arg9-bradykinin.

Abstract: 1. The mechanisms modulating the spontaneous induction of contractile responses to agonists of the B1-receptors for kinins have been studied by submitting the rabbit isolated aorta preparation to various in vitro treatments. Des-Arg9-bradykinin (Des-Arg9-BK), applied after 6 h of in vitro incubation was the standard stimulus to monitor this up-regulation process. 2. Specific inhibition of the development of the contractile response to des-Arg9-BK was obtained by exposing tissues continuously to dexamethasone, dexamethasone sodium phosphate (DSP) or cortisol, but not to oestradiol. The maximal extent of the inhibition obtained at high concentrations of glucocorticoids was 86%. 3. No gross inhibition of protein synthesis was observed in the presence of DSP as monitored by [35S]-methionine incorporation into incubated pieces of rabbit aorta. 4. In vivo pretreatment of rabbits with DSP did not reduce further the development of the responses in vitro. DSP applied 15 min before the 6 h recording did not antagonize the contractile effect of the BK fragment. 5. Interleukin 1 (IL-1) and interleukin 2 (IL-2) applied in vitro for the first 3 h of incubation increased the development of the contractile response to des-Arg9-BK. 6. Arachidonic acid (AA), nordihydroguaiaretic acid, tumour necrosis factor-alpha (TNF) and transforming growth factor-beta (TGF-beta) failed to influence the spontaneous development of the response to kinins. 7. Continuous exposure to DSP (100 microM) markedly inhibited the action of stimulants in this system: IL-1, IL-2, epidermal growth factor and muramyl dipeptide. Moreover, the presence of AA (30 microM) did not prevent the inhibitory effect of DSP (100 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Lessons From Sudden Coronary Death A Comprehensive Morphological Classification Scheme for Atherosclerotic Lesions

Abstract: This review will reconsider the current paradigm for understanding the critical, final steps in the progression of atherosclerotic lesions. That scheme, largely an outgrowth of observations of autopsy tissues by Davies and colleagues,1 2 asserts that the cause of death in atherosclerotic coronary artery disease is rupture of an advanced atherosclerotic lesion. Although this assumption may be partially true, recent autopsy studies suggest that it is incomplete. To reconsider this paradigm, we reexamined the morphological classification scheme for lesions proposed by the American Heart Association (AHA).3 4 This scheme is difficult to use for 2 reasons. First, it uses a very long list of roman numerals modified by letter codes that are difficult to remember. Second, it implies an orderly, linear pattern of lesion progression. This tends to be ambiguous, because it is not clear whether there is a single sequence of events during the progression of all lesions. We have therefore tried to devise a simpler classification scheme that is consistent with the AHA categories but is easier to use, able to deal with a wide array of morphological variations, and not overly burdened by mechanistic implications. The current paradigm is based on the belief that type IV lesions, or “atheromas,” described by the AHA are stable because the fatty, necrotic core is contained by a smooth muscle cell–rich fibrous cap. Virchow’s analysis5 in 1858 pointed out that historically, the term “atheroma” refers to a dermal cyst (“Grutzbalg”), a fatty …

Molecular Regulation of Vascular Smooth Muscle Cell Differentiation in Development and Disease

Abstract: The focus of this review is to provide an overview of the current state of knowledge of molecular mechanisms/processes that control differentiation of vascular smooth muscle cells (SMC) during normal development and maturation of the vasculature, as well as how these mechanisms/processes are altered in vascular injury or disease. A major challenge in understanding differentiation of the vascular SMC is that this cell can exhibit a wide range of different phenotypes at different stages of development, and even in adult organisms the cell is not terminally differentiated. Indeed, the SMC is capable of major changes in its phenotype in response to changes in local environmental cues including growth factors/inhibitors, mechanical influences, cell-cell and cell-matrix interactions, and various inflammatory mediators. There has been much progress in recent years to identify mechanisms that control expression of the repertoire of genes that are specific or selective for the vascular SMC and required for its differentiated function. One of the most exciting recent discoveries was the identification of the serum response factor (SRF) coactivator gene myocardin that appears to be required for expression of many SMC differentiation marker genes, and for initial differentiation of SMC during development. However, it is critical to recognize that overall control of SMC differentiation/maturation, and regulation of its responses to changing environmental cues, is extremely complex and involves the cooperative interaction of many factors and signaling pathways that are just beginning to be understood. There is also relatively recent evidence that circulating stem cell populations can give rise to smooth muscle-like cells in association with vascular injury and atherosclerotic lesion development, although the exact role and properties of these cells remain to be clearly elucidated. The goal of this review is to summarize the current state of our knowledge in this area and to attempt to identify some of the key unresolved challenges and questions that require further study.

Physiology of local renin-angiotensin systems.

Abstract: Since the first identification of renin by Tigerstedt and Bergmann in 1898, the renin-angiotensin system (RAS) has been extensively studied. The current view of the system is characterized by an increased complexity, as evidenced by the discovery of new functional components and pathways of the RAS. In recent years, the pathophysiological implications of the system have been the main focus of attention, and inhibitors of the RAS such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin (ANG) II receptor blockers have become important clinical tools in the treatment of cardiovascular and renal diseases such as hypertension, heart failure, and diabetic nephropathy. Nevertheless, the tissue RAS also plays an important role in mediating diverse physiological functions. These focus not only on the classical actions of ANG on the cardiovascular system, namely, the maintenance of cardiovascular homeostasis, but also on other functions. Recently, the research efforts studying these noncardiovascular effects of the RAS have intensified, and a large body of data are now available to support the existence of numerous organ-based RAS exerting diverse physiological effects. ANG II has direct effects at the cellular level and can influence, for example, cell growth and differentiation, but also may play a role as a mediator of apoptosis. These universal paracrine and autocrine actions may be important in many organ systems and can mediate important physiological stimuli. Transgenic overexpression and knock-out strategies of RAS genes in animals have also shown a central functional role of the RAS in prenatal development. Taken together, these findings may become increasingly important in the study of organ physiology but also for a fresh look at the implications of these findings for organ pathophysiology.

Vascular Smooth Muscle Cells in Atherosclerosis

Abstract: The historical view of vascular smooth muscle cells (VSMCs) in atherosclerosis is that aberrant proliferation of VSMCs promotes plaque formation, but that VSMCs in advanced plaques are entirely beneficial, for example preventing rupture of the fibrous cap. However, this view has been based on ideas that there is a homogenous population of VSMCs within the plaque, that can be identified separate from other plaque cells (particularly macrophages) using standard VSMC and macrophage immunohistochemical markers. More recent genetic lineage tracing studies have shown that VSMC phenotypic switching results in less-differentiated forms that lack VSMC markers including macrophage-like cells, and this switching directly promotes atherosclerosis. In addition, VSMC proliferation may be beneficial throughout atherogenesis, and not just in advanced lesions, whereas VSMC apoptosis, cell senescence, and VSMC-derived macrophage-like cells may promote inflammation. We review the effect of embryological origin on VSMC behavior in atherosclerosis, the role, regulation and consequences of phenotypic switching, the evidence for different origins of VSMCs, and the role of individual processes that VSMCs undergo in atherosclerosis in regard to plaque formation and the structure of advanced lesions. We think there is now compelling evidence that a full understanding of VSMC behavior in atherosclerosis is critical to identify therapeutic targets to both prevent and treat atherosclerosis.

Intraplaque hemorrhage and progression of coronary atheroma.

Abstract: BackgroundIntraplaque hemorrhage is common in advanced coronary atherosclerotic lesions The relation between hemorrhage and the vulnerability of plaque to disruption may involve the accumulation of free cholesterol from erythrocyte membranes MethodsWe stained multiple coronary lesions from 24 randomly selected patients who had died suddenly of coronary causes with an antibody against glycophorin A (a protein specific to erythrocytes that facilitates anion exchange) and Mallory's stain for iron (hemosiderin), markers of previous intraplaque hemorrhage Coronary lesions were classified as lesions with pathologic intimal thickening, fibrous-cap atheromas with cores in an early or late stage of necrosis, or thin-cap fibrous atheromas (vulnerable plaques) The arterial response to plaque hemorrhage was further defined in a rabbit model of atherosclerosis ResultsOnly traces of glycophorin A and iron were found in lesions with pathologic intimal thickening or fibrous-cap atheromas with cores in an early stage