Pulmonary vascular resistance is the resistance against blood flow from the pulmonary artery to the left atrium. It is most commonly modeled using a modification of Ohm’s law (figure 1).
As seen in figure 1, input pressure represents the mean pulmonary arterial pressure (15 mmHg). The output pressure represents the pulmonary venous pressure, which is also equivalent to the pulmonary capillary wedge pressure or left atrial pressure (5 to 6 mmHg). Total blood flow represents the cardiac output (5 to 6 L/min). A normal value for pulmonary vascular resistance using conventional units is 0.25–1.6 mmHg·min/l. Pulmonary vascular resistance can also be represented in units of dynes/sec/cm5 (normal = 37-250 dynes/sec/cm5).
Poiseuille’s law has also been used to model PVR (Figure 2). In this equation, l represents the length of the tube or vessel, r its radius, and n the viscosity of the fluid. Poiseuille’s law clarifies the impact of the radius on resistance. For example, a 50% reduction in radius increases the resistance 16-fold. However, both Ohm’s law and Poiseuille’s law are imperfect approximations of PVR. Both equations assume that blood flow is constant and linear, but it is pulsatile and laminar in reality. Pulmonary blood vessels are not rigid cylinders and expand to accommodate increased flow. Additionally, the non-homogenous nature of blood makes it difficult to ascertain a single value for viscosity. Blood viscosity also varies with shear rate.
The pressure drop from the pulmonary arteries to the left atrium is approximately 10 mmHg compared against a 100 mmHg pressure gradient in the systemic circulation. Therefore, PVR is one-tenth of the resistance of systemic circulation. Low PVR maximizes the distribution of blood to the peripheral alveoli and ultimately allows for proper gas exchange. Additionally, low resistance allows for the pulmonary system to pump the entire cardiac output at low pressures. Most of the total vascular resistance and distribution of blood flow in the pulmonary circuit resides in the capillaries rather than the vessels that are involved in active vasoconstriction. However, approximations generally divide pulmonary resistance equally between arteries, capillaries, and veins. Because resistance increases in the capillaries, the largest drop in pulmonary pressure occurs here, and to a lesser extent, in the small pulmonary arteries in contrast with the systemic circulation where the largest pressure drop occurs in the arterioles.
Multiple mechanisms regulate and contribute to pulmonary vascular resistance. Broad categories include pulmonary vascular pressure, lung volume, gravity, smooth muscle tonicity, and alveolar hypoxia.
Pulmonary Intravascular Pressure
As cardiac input increases, for example, during exercise, the pulmonic circulation must adapt to accommodate this increased forward flow. Therefore, pulmonary intravascular pressure and pulmonary vascular resistance are inversely related. Experiments have shown that increasing the pulmonary arterial pressure while holding left atrial pressure constant results in a decrease in pulmonary vascular resistance. This decrease occurs via two mechanisms: capillary recruitment and capillary distension.
The first mechanism that occurs is capillary recruitment. At baseline, some of the pulmonary capillaries are partially or entirely closed and allow no blood flow. Capillary recruitment is the opening of these closed capillaries during states of increased blood flow. Distribution of flow over a greater cross-sectional surface area reduces the overall vascular resistance. Recruitment usually occurs in zone 1 of the lung (apices), where the capillary pressures are the lowest.
Capillary distension is the second mechanism and involves the widening of the capillaries to accommodate increased blood flow. The Ovular vessels become more circular, which is the predominant mechanism for maintaining low PVR at higher pulmonary arterial pressures.
Alveolar pressures and volumes greatly influence pulmonary vascular resistance. The effect of lung volume depends on the type of vessel. Extra-alveolar vessels run through the lung parenchyma. These vessels have smooth muscle and elastic tissue, which inherently reduces vessel circumference by counteracting distension. As the lung expands, the diameter of these vessels increases via radial traction of the vessel walls. Therefore, vascular resistance is low at large lung volumes. During lung collapse, there is increased resistance through the vessels due to the unopposed action of vessel elasticity. Critical opening pressure represents the air pressure needed to allow blood flow through extra-alveolar capillaries. This concept is applicable when modeling vascular resistance in a collapsed lung.
Alveolar capillaries include capillaries and vessels in the corner of the alveolar walls. The determinant of the amount of distension within these vessels is their transmural pressure (Figure 3).
Alveolar pressure is highest in zone 1 (near the apices) and lowest in zone 3 (near the bases). During inspiration, alveolar pressure rises, which compresses the surrounding alveolar capillaries. Even with the increased right heart return associated with inspiration, stretching and thinning of the alveolar walls reduces capillary caliber and ultimately leads to an increase in PVR at large lung volumes. PVR is highest at total lung capacity (TLC), high at residual volume (RV), and lowest at functional residual capacity (FRC) (Figure 4).
Figure 5 illustrates the different zones of the lung. PVR is greatest at zone 1 since the elevated alveolar pressure increases the inward transmural pressure on the alveolar-capillary. The capillary becomes collapsible, and the resistance increases. PVR is lowest at zone 3, where the arterial pressure is higher than the alveolar pressure, causing an increased outward transmural pressure and increased vessel caliber.
Hypoxia within alveoli induces vasoconstriction within the lung vasculature. This homeostatic mechanism allows the lungs to shunt blood to more oxygenated lung segments, thus allowing for enhanced ventilation/perfusion matching, which in turn improves oxygen delivery throughout the body. This mechanism becomes abundantly important when the lungs are exposed to disruptive processes, such as consolidation (e.g., pneumonia) or blockage within the vasculature (e.g., pulmonary emboli), thereby allowing for appropriate compensation. The theory is that this response begins at the molecular level, in which a mitochondrial sensor utilizes redox coupling reactions to alter the elasticity of pulmonary artery smooth muscle cells (PASMC). The redox reactions lead to the depolarization of PASMC via activation of voltage-gated calcium channels and inhibition of potassium channels, which leads to decreased elasticity within arterioles of hypoxic lung segments. Further, if there is sustained hypoxia, alternative pathways can become activated (e.g., rho kinase), and the release of chemokines (e.g., hypoxia-inducible factor (HIF)-1alpha) can occur, which enhances the vasoconstrictive effects as well as remodeling of the vasculature.
Smooth Muscle Tonicity
Generally, the pulmonary circulation has a low vascular tone; this is due to pulmonary vessels having proportionately less smooth muscle compared to vessels of similar diameter in other organs. Compared to systemic vessels, the smooth muscle tissue in pulmonary vessels is distributed less evenly in the tunica intima. The pulmonary veins are also more compliant than systemic arteries due to lack of tissue around small vessels, reduced elastin and collagen fibers, and reduced smooth muscle content. A phenomenon that is demonstrated by the pressure gradient observed between the right and left ventricles.
Pulmonary arteries are both elastic and muscular. These arteries contain smooth muscle within the tunica media that is surrounded by internal and external elastic laminae. These include the pulmonary artery trunk, main branches, and extra-alveolar vessels. Larger, peri-bronchial arteries are more muscular (>2mm). Peri-bronchial arteries lie within the lung lobules. These extra-alveolar arteries control PVR through neural, humoral, or gaseous control. As the vessels become smaller, smooth muscle content decreases. The smooth muscle takes on a spiral shape and becomes the pulmonary arterioles that supply alveoli and alveolar ducts. If smooth muscle exceeds 5% of the external diameter, it is considered pathological.
Pulmonary arteries have more smooth muscle relative to veins and represent the primary sites of constriction by vasoactive mediators. Capillaries are devoid of vasomotor control. Factors that cause increased tone and thereby increased PVR include serotonin, epinephrine, norepinephrine, histamine, ATP, adenosine, neurokinin A, endothelin, angiotensin, thromboxane A/Prostaglandins/Leukotrienes (LTB). Most of these factors act through a G-protein coupled pathway, which activates myosin contraction. Neuronally, pulmonary constriction is under the mediation of the sympathetic nervous system through the stimulation of a1 adrenergic receptors.
Factors that decrease smooth muscle tonicity and decrease PVR include acetylcholine and isoproterenol, prostacyclin (PGI), bradykinin, vasopressin, ANP, substance P, VIP, histamine (during adrenaline response). Most of the factors act through activation of cyclic adenosine 3’,5’ monophosphate (cAMP). cAMP de-phosphorylates myosin and reduces calcium levels, causing relaxation of smooth muscle. Pulmonary endothelial cells cause relaxation through the production of nitric oxide (NO). NO diffuses through smooth muscle cells, activates cyclic guanosine 3’, 5’ monophosphate (cGMP), which causes smooth muscle relaxation through the de-phosphorylation of myosin. Additionally, stimulus from the parasympathetic nervous system via the vagus nerve on M muscarinic receptors in the vasculature cases NO-dependent vasodilation.
Disease processes that cause chronic hypoxia will increase pulmonary vascular resistance through hypoxic pulmonary vasoconstriction. These include pulmonary edema, pulmonary emboli, and cardiovascular disease. Pulmonary edema causes alveoli to shrink due to increased surface tension, causing hypoxemia and shunting of blood to areas of greater ventilation. Hypoxia will induce vasoconstriction leading to pulmonary hypertension and increased vascular resistance. Peri-bronchial cuffing increases the resistance of extra-alveolar vessels while alveolar edema compresses and distorts capillaries. Recruitment and distension of pulmonary capillaries allow for a large reserve in the pulmonary circulation. Half of the pulmonary circulation can become obstructed before there is a significant detectable rise in pulmonary pressures. While the mechanism of increased PVR secondary to pulmonary embolism is still under investigation, the current thinking is that it results from serotonin release from platelets.
Cardiovascular disease may also lead to increased pulmonary vascular resistance. Left heart valvular disease, such as mitral stenosis or regurgitation, leads to elevation of pressures in the left atrium and, ultimately, the pulmonary veins. Increases in pulmonary capillary pressures over a long period lead to smooth muscle hypertrophy and fibrosis of pulmonary vasculature. These changes, in turn, cause pulmonary arterial hypertension and eventually cor pulmonale.
Increased pulmonary vascular resistance is the leading cause of pulmonary hypertension. Furthermore, increased PVR can lead to pulmonary hypertension, which can further lead to increased PVR due to chronic vasoconstriction, vascular remodeling, endothelial thickening, arteriolar smooth muscle hypertrophy, and increased thromboxane and endothelin-1 production. Pulmonary hypertension is a mean pressure greater than 25 mmHg and a PVR greater than 3 mmHg·min/l. This measurement is obtained through a right heart catheterization (e.g., Swan-Ganz catheters). Increased PVR may occur secondary to processes that cause hypoxic pulmonary vasoconstriction or neurally mediated vasoconstriction (catecholamine release). These processes include chronic obstructive pulmonary disease, emphysema, pulmonary fibrosis, cystic fibrosis, sleep apnea, lupus, scleroderma, rheumatoid arthritis, and HIV. Vascular obstruction secondary to venous thromboembolism, air embolus, amniotic fluid, and schistosomiasis also causes an increase in pulmonary vascular resistance, thereby leading to pulmonary hypertension. Obliterative processes such as pulmonary vasculitides destroy capillary beds and ultimately increase PVR in certain areas.