Physiology of the vascular system

Vascular function modulates total and peripheral resistance to control blood flow by regulating arterial vasculature tone and venous capacitance and return. Fast adaptation of blood flow to different physiological conditions, even daily routine activities as standing up or exercising, is crucial to an appropriate distribution of blood flow along the circulation system to preserve adequate pressures and metabolic tissue needs [18], [19]. Elastic arteries, such as the aorta or the common carotid arteries, have a relevant task in the distribution of CO since they act as a reserve of blood and energy to keep flow during diastole, when the ejection ceases. This phenomenon is known as the windkessel effect [26] and it helps to damp the pulsatility of pressure in smaller vessels and capillaries (see figure 1.9).

1.2.2.1 Regulation of blood flow

Vascular tone is inversely proportional to arterial size, being highest in the smaller, muscular arteries and arterioles, which are major determinants of peripheral resistance and local blood flow. Several physiological mechanisms influence the level of vascular tone and, hence, lumen diameter and resistance.

All these mechanisms eventually focus on the modulation of vascular smooth muscle responding to modifications of the mechanical forces at the vascular wall or the release of neurotransmitters or metabolites by surrounding tis-sues. Particularly, myogenic tone is the intrinsic ability of vascular smooth muscle to constrict in response to pressure or stretch. On the other hand, the endothelium releases vasoactive factors that influence vascular tone [16], [20].

Although myogenic responses in arteries, arterioles and veins are re-ported, the mechanisms behind this effect are still elusive. On the other hand, endothelium influences vascular tone by releasing vasoactive molecules, such as nitric oxide (NO), peptide endothelin and dilator and constrictor prostaglandins (see figure 1.10), either through cholinergic, physical or chem-ical stimulation. An important example of physchem-ical stimulation is shear stress

Figure 1.9: Graphical depiction of blood pressure values and changes through-out the vascular system.Blood pressure in the arterial tree is pulsatile due to the pump function of the heart and arterial mechanical properties. At this portion of the vascular system, systolic, diastolic, mean and pulse pressure are identified (pulsatile red line). Blood pressure is reduced in arterioles (straight red line) and capillaries (purple line) and pulsatility ceases. Blood pressure continues to decrease through the venous return system (blue line) until blood reaches the right atrium of the heart. Adapted fromhttps://commons.wikimedia.org/wiki/File:

2109_Systemic_Blood_Pressure.jpg. By OpenStax College [CC BY 3.0 (https://creativecommons.org/licenses/by/3.0)].

that acts on the vascular endothelium as a stimulant for vascular tone regula-tion in the short term and arterial remodelling in the long term, according to tissue blood flow demand [16], [20].

Regarding the control of peripheral blood flow and resistance, another important factor to consider is autonomic regulation. Arterial pressure is partly controlled by direct sympathetic innervation. Sympathetic efferent activity is dictated by sophisticated interactions from different portions of the nervous system and feedback signals from cardiovascular mechano- and chemoreceptors localised in the heart, the aortic arch and the carotid sinuses.

During sympathetic activation (i.e., the “fight or flight reaction”), blood pressure (BP) rockets, venous return raises and, thus, CO is redistributed.

In contrast, parasympathetic activity typically generates opposite responses:

vascular relaxation and reduced cardiac rate and output. However, the role of the parasympathetic system is considered secondary in peripheral vascular regulation [16], [17], [19].

Moreover, sympathetic vasoconstrictor and vasodilator fibres respond to emotional stress and/or to postural changes and are involved in the regulation

Figure 1.10: Postulated pathways of vasodilation. There are three relevant vasodilation pathways: The endothelin pathway involving peptides known as endothelins that constrict blood vessels and promote platelet aggregation; The nitric oxide (NO) pathway in which NO is produced in endothelial cells from the amino acid L-arginine modulating vasodilation and adhesion of both platelets and mono-cytes to the vascular wall; The prostacyclin pathway, which involves the synthesis of a prostaglandin (derived from the arachidonic acid) that is an effective vasodilator and inhibits blood platelet activation. cAMP: cyclic adenosine monophosphate;

cGMP: cyclic guanosine monophosphate. Adapted from the reference: Reprinted from Humbert M, Sitbon O, Simonneau G. 2004. Treatment of pulmonary arterial hypertension. N Engl J Med, 351:1425-36. Copyright © 2004 with permission from Massachusetts Medical Society. Adapted from the reference: A review of pulmonary arterial hypertension: Role of ambrisentan - Scientific Figure on ResearchGate.

Available from: https://www.researchgate.net/figure/Postulated-pathways-in-the-pathobiology-of-pulmonary-arterial-hypertension-PAH-and-drug_fig1_6254474 [accessed 20 Oct, 2019] via license: Creative Commons Attribution-NonCommercial 4.0 International [29].

of body temperature. Notably, local metabolites produced during exercise or ischemia have a powerful vasodilator effect in vessels within skeletal muscle.

Not only these metabolites stimulate the release of endothelial factors (NO and prostacyclin) but their incremental effect in flow operates as a (shear stress) stimulus for the further release of endothelial vasoactive substances.

However, metabolic regulation is only one of several mechanisms, including neural, myogenic and humoral/endothelial, for peripheral blood flow con-trol, since it concerns a complex interaction determined partly by ambient conditions [17], [19], [20].

The ability of most vascular beds to maintain a constant blood flow over a range of systemic arterial pressures is known as autoregulation, and it is determined by the capability of the resistance vessels to constrict in response to a pressure increase and to dilate due to a pressure fall. Autoregulation is especially well developed in cerebral, coronary, and renal circulations [19], [20].

Pressure-Flow waveforms

Figure 1.11: Graphical description of pressure (red) and flow (blue) waves align-ment to perform Fourier analysis.At the aorta (left) and carotid (right) arteries.

Adapted from F. Londono-Hoyos, P. Zamani, M. Beraun, I. Vasim, P. Segers and J.

A. Chirinos, ‘Effect of organic and inorganic nitrates on cerebrovascular pulsatile power transmission in patients with heart failure and preserved ejection fraction’, Physiological measurement, vol. 39, no. 4, p. 044001, 2018 [3].

Peripheral resistance also impacts arterial flow and pressure waves. Dur-ing systole, the compliant aorta stores a portion of the SV that is pushed forward by elastic recoil during diastole. When the blood arrives to the high resistance arterioles, a part is transmitted while other part is reflected to the arterial tree. In terms of flow, the reflected wave subtracts from the forward wave, producing a short period of reversal flow in early diastole unless peri-pheral resistance is low [20]. Instead, the pressure reflected wave adds to

the forward wave, producing an upward deflection on the downslope of the pressure pulse. This effect accounts for the systolic pressure amplification, diastolic pressure reduction and pulse pressure widening observed as blood flows from the aorta to the peripheral arteries. Even if wave reflections occur through all the arterial tree at vessel branches, bifurcations and narrowing, high-resistance vessels are a pivotal factor [20]. Moreover, waveform modifi-cations due to reflections are more evident in peripheral arteries [20]. Fourier analysis of pressure and flow waveforms delivers supplementary information about the peripheral cardiovascular system (see figure 1.11 and Chapters 3 and 5).