When acetylcholine or other vasodilator agents stimulate endothelial cells, they release nitric oxide (NO). This release of NO only causes vasodilation in blood vessels that have an endothelium. NO is synthesized from L-arginine and activates guanylyl cyclase in vascular smooth muscle, leading to an increase in cyclic guanosine monophosphate (cGMP) concentration. This increase in cGMP concentration results in relaxation by decreasing myofilament sensitivity to calcium ions (Ca++). The shear stress of blood flow on the endothelium can also stimulate the release of NO. Nitroprusside, a drug, can increase cGMP levels by directly acting on vascular smooth muscle. Acetylcholine also stimulates the release of an unknown endothelium-dependent hyperpolarizing factor that causes relaxation of adjacent smooth muscle. The mechanism by which this factor reaches vascular smooth muscle is unclear. Endothelial cells have diverse ways of communicating with vascular smooth muscle. The endothelium can synthesize endothelin, which is a potent vasoconstrictor peptide. Endothelin affects vascular tone, blood pressure, and may play a role in pathological states such as atherosclerosis, pulmonary hypertension, congestive heart failure, and renal failure.

The capillary endothelium plays a passive role in the movement of solvent and solute across the capillary wall. This movement occurs through three processes: diffusion, filtration, and pinocytosis. Diffusion is the most important process for transcapillary exchange, while pinocytosis is the least important. Under normal conditions, diffusion accounts for the majority of water movement across the capillary wall, with only a small amount occurring through filtration. Diffusion is crucial for the exchange of gases, substrates, and waste products between capillaries and tissue cells. Fick's law describes the process of diffusion.

In terms of transport from capillaries to tissue, there are two scenarios. In flow-limited transport, small water-soluble inert tracer particles reach negligible concentrations after passing a short distance down the capillary. Larger particles with similar properties travel farther along the capillary before reaching an insignificant intracapillary concentration. Both substances cross the interstitial fluid and reach the parenchymal tissue. Smaller particles are more likely to be taken up by the tissue cells due to their size. The largest particles cannot penetrate the capillary pores and can only escape from the capillary lumen through pinocytotic vesicle transport. An increase in blood flow volume or an increase in capillary density can increase the supply of diffusible solutes to the tissues. It is important to note that capillary permeability is greater at the venous end of the capillary due to a larger number of pores in this region.

In diffusion-limited transport, when the distance between capillaries and parenchymal tissue is large due to edema or low capillary density, diffusion becomes a limiting factor in solute transport from the capillary to tissue, even at high rates of capillary flow.
Fig. 17.24 ). When endothelial cells are stimulated by acetylcholine or other vasodilator agents (e.g., adenosine triphosphate [ATP], bradykinin, serotonin, substance P, histamine), NO is released. These agents do not cause vasodilation in blood vessels lacking the endothelium. NO (synthesized from L-arginine) activates guanylyl cyclase in vascular smooth muscle to increase the concentration of cyclic guanosine monophosphate (cGMP), which produces relaxation by decreasing myofilament sensitivity to [Ca++]. Release of NO can be stimulated by the shear stress of blood flow on the endothelium. The drug nitroprusside also increases cGMP by acting directly on vascular smooth
Acetylcholine also stimulates the release of an endothelium-dependent hyperpolarizing factor that underlies the relaxation of adjacent smooth muscle. Although arachidonic acid metabolites have been suggested, the factor remains unknown. Moreover, how the factor reaches vascular smooth muscle (diffusion through the extracellular space or passage via myoepithelial junctions) is unclear. Nevertheless, there are diverse ways by which endothelial cells communicate with vascular smooth muscle.
The endothelium can also synthesize endothelin, a potent vasoconstrictor peptide. Endothelin affects vascular tone and blood pressure and may be involved in pathological states, including atherosclerosis, pulmonary hypertension, congestive heart failure, and renal failure.
Passive Role of the Capillary Endothelium
Solvent and solute move across the capillary endothelial wall by three processes: diffusion, filtration, and pinocytosis. Diffusion is the most important process for transcapillary exchange, and pinocytosis is the least important.
Diffusion. Under normal conditions, only approximately 0.06 mL of water per minute moves across the capillary wall per 100 g of tissue as a result of filtration. In contrast, 300 mL of water per minute per 100 g of tissue moves across the capillary wall by diffusion. Thus diffusion is the key factor in providing exchange of gases, substrates, and waste products between capillaries and tissue cells.
The process of diffusion is described by Fick’s law (see also
Equation 17.17
J = quantity of a substance moved per unit time
A = cross-sectional area of the diffusion pathway
ΔC = concentration gradient of the solute •Fig. 17.25 Flowand Diffusion-Limited Transport From Capillaries (Cap) to Tissue. A, Flow-limitedtransport.Thesmallestwater-solubleinerttracerparticles(blue dots) reachnegligibleconcentrationsafterpassingonlyashortdistancedownthecapillary.Largerparticles(brown dots) withsimilarpropertiestravelfartheralongthecapillarybeforereachinganinsignificantintracapillaryconcentration.Bothsubstancescrosstheinterstitialfluid(ISF)andreachtheparenchymaltissue(Cell).Becauseoftheirsize,moreofthesmallerparticlesaretakenupbythetissuecells.Thelargestparticles(red circles) cannotpenetratethecapillaryporesandhencedonotescapefromthecapillarylumenexceptbypinocytoticvesicletransport.Anincreaseinthevolumeofbloodfloworanincreaseincapillarydensityincreasestissuesupplyofthediffusiblesolutes.Notethatcapillarypermeabilityisgreateratthevenousendofthecapillary(alsointhevenule,notshown)becauseofthelargernumberofporesinthisregion.B, Diffusion-limitedtransport.Whenthedistancebetweencapillariesandparenchymaltissueislargeasaresultofedemaorlowcapillarydensity,diffusionbecomesalimitingfactorinsolutetransportfromcapillarytotissue,evenathighratesofcapillaryflow.