Intussusceptive microvascular growth: a common alternative to capillary sprouting.

Intussusceptive capillary growth represents a new principle for microvascular growth as described in the lungs of growing rats. According to this concept, the capillary network expands by the formation of slender transcapillary tissue pillars, which give rise to new vascular meshes. The process was first observed in Mercox casts of the lung microvasculature, which revealed the existence of multiple tiny holes with diameters around 1.5 microns. Consecutive transmission electron microscopic investigation of serial sections demonstrated that the holes corresponded to slender tissue pillars (Burri and Tarek, 1990). The corrosion cast technique thus appears to be an adequate screening method for intussusceptive growth. In the present investigation, Mercox casts of various vascular systems, namely, those of the eye, submandibular gland, heart, liver, stomach, small and large intestine, trachea, kidney, uterus and ovary were prepared from rats aged between 4 and 9 weeks in order to screen them for the existence of the typical tiny holes representing tissue pillars. In all organs investigated, these structures were observed in various locations to a variable degree. They were mainly encountered within dilated vascular segments or at triple or quadruple branching points of the circulation. Even in capillary networks with a three-dimensional arrangement could these pillars be detected. Intussusception thus appears to be a principle of growth appertaining to many vascular systems.

Effect of a Tibetan herbal mixture on microvascular endothelial function, heart rate variability and biomarkers of inflammation, clotting and coagulation

In this 6-week prospective, randomized, placebo-controlled and double-blind study, we investigated the effects of a natural herbal remedy based on a recipe from Tibet (Padma® 28), on microvascular endothelial function, heart rate variability and biomarkers of inflammation, clotting and coagulation in 80 coronary artery disease (CAD) patients (age 66 ± 8 years) on guideline-based medication for secondary prevention. We found no significant effects of Padma 28 and conclude that the addition of Padma 28 to guideline-based secondary prevention treatment of CAD did not lead to significant effects on important surrogate markers in elderly male CAD patients.

Renal microvascular assembly and repair: power and promise of molecular definition.

Developmental assembly of the renal microcirculation is a precise and coordinated process now accessible to experimental scrutiny. Although definition of the cellular and molecular determinants is incomplete, recent findings have reframed concepts and questions about the origins of vascular cells in the glomerulus and the molecules that direct cell recruitment, specialization and morphogenesis. New findings illustrate principles that may be applied to defining critical steps in microvascular repair following glomerular injury. Developmental assembly of endothelial, mesangial and epithelial cells into glomerular capillaries requires that a coordinated, temporally defined series of steps occur in an anatomically ordered sequence. Recent evidence shows that both vasculogenic and angiogenic processes participate. Local signals direct cell migration, proliferation, differentiation, cell-cell recognition, formation of intercellular connections, and morphogenesis. Growth factor receptor tyrosine kinases on vascular cells are important mediators of many of these events. Cultured cell systems have suggested that basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF) promote endothelial cell proliferation, migration or morphogenesis, while genetic deletion experiments have defined an important role for PDGF beta receptors and platelet-derived growth factor (PDGF) B in glomerular development. Receptor tyrosine kinases that convey non-proliferative signals also contribute in kidney and other sites. The EphB1 receptor, one of a diverse class of Eph receptors implicated in neural cell targeting, directs renal endothelial migration, cell-cell recognition and assembly, and is expressed with its ligand in developing glomeruli. Endothelial TIE2 receptors bind angiopoietins (1 and 2), the products of adjacent supportive cells, to signals direct capillary maturation in a sequence that defines cooperative roles for cells of different lineages. Ultimately, definition of the cellular steps and molecular sequence that direct microvascular cell assembly promises to identify therapeutic targets for repair and adaptive remodeling of injured glomeruli.

Microvascular and tissue oxygen gradients in the rat mesentery

One of the most important functions of the blood circulation is O2 delivery to the tissue. This process occurs primarily in microvessels that also regulate blood flow and are the site of many metabolic processes that require O2. We measured the intraluminal and perivascular pO2 in rat mesenteric arterioles in vivo by using noninvasive phosphorescence quenching microscopy. From these measurements, we calculated the rate at which O2 diffuses out of microvessels from the blood. The rate of O2 efflux and the O2 gradients found in the immediate vicinity of arterioles indicate the presence of a large O2 sink at the interface between blood and tissue, a region that includes smooth muscle and endothelium. Mass balance analyses show that the loss of O2 from the arterioles in this vascular bed primarily is caused by O2 consumption in the microvascular wall. The high metabolic rate of the vessel wall relative to parenchymal tissue in the rat mesentery suggests that in addition to serving as a conduit for the delivery of O2 the microvasculature has other functions that require a significant amount of O2.

Transcytosis of α1-acidic glycoprotein in the continuous microvascular endothelium

By using perfusions and bolus administration, coupled with postembedding immunocytochemical procedures, we have identified the structures involved in the transport of derivatized orosomucoid (α1-acidic glycoprotein) across the continuous microvascular endothelium of the murine myocardium. Our findings indicate that: (i) monomeric orosomucoid binds to the luminal surface of the endothelium; (ii) it is restricted to caveolae during its transport across the endothelium; (iii) it is detected in the perivascular spaces at early time points (by 1 min) and in larger quantities at later time points (>5 min) from the beginning of its perfusion or its intravascular administration; (iv) no orosomucoid molecules are found in the intercellular junctions or at the abluminal exits of interendothelial spaces; and (v) the vesicular transport of orosomucoid is strongly inhibited by N-ethylmaleimide (>80%). Because, by size and shape, the orosomucoid qualifies as a preferential probe for the postulated small pore system, our results are discussed in relation to the pore theory of capillary permeability.

Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: Role of vascular endothelial growth factor

The sequence of events that leads to tumor vessel regression and the functional characteristics of these vessels during hormone–ablation therapy are not known. This is because of the lack of an appropriate animal model and monitoring technology. By using in vivo microscopy and in situ molecular analysis of the androgen-dependent Shionogi carcinoma grown in severe combined immunodeficient mice, we show that castration of these mice leads to tumor regression and a concomitant decrease in vascular endothelial growth factor (VEGF) expression. Androgen withdrawal is known to induce apoptosis in Shionogi tumor cells. Surprisingly, tumor endothelial cells begin to undergo apoptosis before neoplastic cells, and rarefaction of tumor vessels precedes the decrease in tumor size. The regressing vessels begin to exhibit normal phenotype, i.e., lower diameter, tortuosity, vascular permeability, and leukocyte adhesion. Two weeks after castration, a second wave of angiogenesis and tumor growth begins with a concomitant increase in VEGF expression. Because human tumors often relapse following hormone–ablation therapy, our data suggest that these patients may benefit from combined anti-VEGF therapy.

Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38

Objective: To determine whether tight control of blood pressure prevents macrovascular and microvascular complications in patients with type 2 diabetes.

Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39

Objective: To determine whether tight control of blood pressure with either a β blocker or an angiotensin converting enzyme inhibitor has a specific advantage or disadvantage in preventing the macrovascular and microvascular complications of type 2 diabetes.